Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[C:3]=1[CH:4]=O.C(=O)([O-])[O-].[K+].[K+].[C:17]([O:21][CH3:22])(=[O:20])[CH2:18][SH:19]>CN(C=O)C>[CH3:22][O:21][C:17]([C:18]1[S:19][C:2]2[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[C:3]=2[CH:4]=1)=[O:20]
Reactant: COC(=O)CS
Reactant: O=Cc1c(Br)cccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(Br)cccc2s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 83.8 %

Procedure:
To the solution of the compound (6.64 g, 25.16 mmol) obtained in Step 1 in DMF (90 ml), potassium carbonate (7.65 g, 55.35 mmol) and methyl thioglycolate (2.7 ml, 30.19 mmol) were added in that order, and then the reaction mixture was heated at reflux with stirring for 6 hours. After the termination of the reaction, the resulting reaction solution was cooled to room temperature, extracted with ethyl acetate, and then washed with water and brine. Subsequently, the reaction solution was dried over MgSO4, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=40:1), thus obtaining the title compound as a white solid (5.72 g, 21.09 mmol, 84%).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:19][N:18]2[C:10]([C:11]3[NH:12][C:13]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[N:14][C:15]=3[N:16]=[C:17]2Cl)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][S:27][CH:28](C)CO.[H-].[Na+].C([O:37][CH2:38][CH3:39])(=O)C>O1CCCC1>[CH2:1]([C@@H:8]1[CH2:19][N:18]2[C:10]([C:11]3[NH:12][C:13]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[N:14][C:15]=3[N:16]=[C:17]2[O:37][CH2:38][CH2:39][CH2:26][S:27][CH3:28])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC1=Nc2nc(C3CCCC3)[nH]c2C2=N[C@H](Cc3ccccc3)CN12
Reactant: CCOC(C)=O
Reactant: CSC(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSCCCOC1=Nc2nc(C3CCCC3)[nH]c2C2=N[C@H](Cc3ccccc3)CN12
Reaction time: 4 h
Yield: 40 %

Procedure:
To a solution of Compound 67a (240 mg, 0.585 mmol) obtained in Example 67 in tetrahydrofuran (2 mL) were added 2-methylthiopropanol (1 mL) and sodium hydride (containing 34% mineral oil, 88 mg, 2.34 mmol), then Compound 67a (240 mg, 0.585 mmol) was further added to the mixture, and stirring was continued at 100° C. for 4 hours. To the reaction mixture was added ethyl acetate, and the mixture was washed twice with water and dried over magnesium sulfate. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (chloroform:methanol=99:1) to obtain the title compound (100 mg, 40%) as an ocher foamy solid.
Reaction SMILES: OC(C(F)(F)F)=O.[C:8]1([CH2:14][CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:23][N:24]([CH:33]1[CH2:37][CH:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:35]([CH:44]=O)[CH2:34]1)[C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O)(=O)C.C(N(CC)C(C)C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:73]CCCl>>[ClH:73].[CH3:23][N:24]([CH:33]1[CH2:37][CH:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:35]([CH2:44][N:20]2[CH2:19][CH2:18][CH:17]([CH2:16][CH2:15][CH2:14][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:22][CH2:21]2)[CH2:34]1)[C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: ClCCCl
Reactant: c1ccc(CCCC2CCNCC2)cc1
Reactant: CN(C(=O)c1ccccc1)C1CC(C=O)C(c2ccccc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CN(C(=O)c1ccccc1)C1CC(CN2CCC(CCCc3ccccc3)CC2)C(c2ccccc2)C1
Product: Cl
Reaction time: 18 h

Procedure:
To a 13×100 mm threaded vial can be added 4-(3-phenylprop-1-yl)piperidine-TFA salt (0.093 mmol). A solution of 1-(RS)-(N-(methyl)-N-(benzoyl)amino)-3-(SR)-(formyl)-4-(SR)-phenylcyclopentane (19 mg, 0.062 mmol) from Step D (derived from the higher Rf isomer in Step C) and acetic acid (0.006 mL, 0.1 mmol) in 1,2-dichloroethane (1 mL) can then be added to the vial. Sequentially, N,N-diisopropylethylamine (0.022 mL, 0.126 mmol) and a solution of sodium triacetoxyborohydride (26 mg, 0.123 mmol) in 1,2-dichloroethane (2 mL) are then added. The vial is sealed with a septum cap, gently shaken and stored at ambient temperature. After 18 hours, solvent is removed by a stream of warm nitrogen and the residue is redissolved in 80% acetonitrile in water. The sample can be purified on a Gilson Combinatorial Chromatography system using a 9.4 mm×25 cm Zorbax SB-C18 column. Fractions are collected based on the UV absorption and analyzed by mass spec to identify the title compound fractions. These are combined and evaporated.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:44]=[CH:43][C:26]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][CH2:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH2:32][CH2:31]2)=[O:28])=[CH:25][C:24]=1[O:45][CH3:46].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C.ClCCl>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:44]=[CH:43][C:26]([C:27]([NH:29][CH:30]5[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][CH2:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH2:32][CH2:31]5)=[O:28])=[CH:25][C:24]=4[O:45][CH3:46])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1cc(C(=O)NC2CCN(CCCS(C)(=O)=O)CC2)ccc1N
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1cc(C(=O)NC2CCN(CCCS(C)(=O)=O)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
A mixture of 0.08 g (0.25 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-20) and 0.112 g (0.30 mmole) of 4-amino-N-[1-(3-methanesulfonyl-propyl)-piperidin-4-yl]-3-methoxy-benzamide and 0.072 g (0.38 mmole) of p-toluenesulfonic acid monohydrate in 3 mL of isopropanol was stirred in a sealed tube at 140 degrees overnight. After cooling, dichloromethane and saturated sodium carbonate were added. The mixture was extracted twice with dichloromethane. The combined organic layers were washed three times with sodium carbonate solution, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-85:15) gave 0.11 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-[1-(3-methanesulfonyl-propyl)-piperidin-4-yl]-3-methoxy-benzamide (I-76) as a white solid.
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[Br:14][CH2:15][CH2:16][CH2:17][CH:18]([OH:23])[C:19]([O:21][CH3:22])=[O:20].C(O)(C)C>CC(C)=O.O>[Br:14][CH2:15][CH2:16][CH2:17][C:18](=[O:23])[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)C(O)CCCBr
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: COC(=O)C(=O)CCCBr
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 92 %

Procedure:
Jones' reagent (CrO3 : 9.58 g, H2SO4 : 8.47 ml, H2O: 36.8 ml) was added to a magnetically stirred solution of Part (3) compound (12.53 g, 59.3 mmole) in acetone (150 ml) at room temperature. The addition was controlled to maintain the temperature below 35° C. After the completion of the addition, the reaction was stirred at room temperature for 45 minutes. Isopropyl alcohol (30 ml) was added dropwise and stirred for 30 minutes. The reaction was then diluted with H2O (500 ml) and the products were extracted with CH2Cl2 (1 l.). The CH2Cl2 layer was washed with brine (100 ml×3) and dried over MgSO4. Filtration and evaporation of solvents gave the title compound (11.4 g, 54.5 mmole, 92%) as a colorless liquid.
Reaction SMILES: CN(C)C=O.P(Cl)(Cl)([Cl:8])=O.[Br:11][C:12]1[CH:17]=CC(NC(=O)CC2C=CC=CC=2)=C[CH:13]=1.Cl[C:29]1[CH:30]=[C:31]([C:35]([C:37]2C=[CH:41][N:40]=[C:39]([C:43](F)(F)F)[CH:38]=2)=O)[CH:32]=[CH:33][CH:34]=1>>[Br:11][C:12]1[CH:17]=[C:38]2[C:39](=[CH:43][CH:13]=1)[N:40]=[C:41]([Cl:8])[C:35]([C:31]1[CH:30]=[CH:29][CH:34]=[CH:33][CH:32]=1)=[CH:37]2
Reactant: O=C(Cc1ccccc1)Nc1ccc(Br)cc1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(c1cccc(Cl)c1)c1ccnc(C(F)(F)F)c1
Solvent: CN(C)C=O
Product: Clc1nc2ccc(Br)cc2cc1-c1ccccc1
Temperature: 80 °C

Procedure:
Into a 50-mL round-bottom flask were placed N,N-dimethylformamide (2.15 g, 29.45 mmol) and phosphoryl trichloride (20.3 g, 132.7 mmol) and the mixture was cooled to 0° C. Then, N-(4-bromophenyl)-2-phenylacetamide (5.7 g, 17.87 mmol, Intermediate 23: step a) was added in portions. The resulting solution was heated at 80° C. for 5 hours, then concentrated under vacuum, followed by dilution with 50 mL of H2O, and then extraction with 3×50 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by FCC (1:10 EtOAc/petroleum ether) to afford the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1.[CH2:15]([NH2:25])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24].[OH-:26].[K+]>C(Cl)CCl>[F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:25][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:8](=[O:9])[C:7]2[CH:11]=[CH:12][C:4]([O:26][C:2]([F:1])([F:13])[F:14])=[CH:5][CH:6]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: [OH-]
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: NCCCCCCCCCN
Agent: [K+]
Solvent: ClCCCl
Product: O=C(NCCCCCCCCCNC(=O)c1ccc(OC(F)(F)F)cc1)c1ccc(OC(F)(F)F)cc1

Procedure:
m.p. 144°-145° C., 12.1 g., was prepared as in Example 1 using 24.6 of 4-trifluoromethoxybenzoyl chloride in 200 ml. ethylene dichloride, 7.9 g. of 1,9-nonanediamine, 60 ml. of 10% aqueous potassium hydroxide solution, 300 ml. of ethylene dichloride and recrystallization from acetonitrile.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[C:15]4[N:16]=[CH:17][N:18]=[CH:19][C:20]=4[N:21]=[C:13]3[NH:12][C:11]([CH3:22])=[C:10]2[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:5][CH:4]=1)#[N:2].[F:28][C:29]([F:40])([F:39])[C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.N1C=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[C:15]4[N:16]=[CH:17][N:18]=[CH:19][C:20]=4[N:21]=[C:13]3[N:12]([C:34]3[CH:33]=[CH:32][CH:31]=[C:30]([C:29]([F:40])([F:39])[F:28])[CH:35]=3)[C:11]([CH3:22])=[C:10]2[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)C1=C(C)Nc2nc3cncnc3n2C1c1ccc(C#N)cc1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nc3cncnc3n2C1c1ccc(C#N)cc1
Reaction time: 12 h

Procedure:
(rac)-Ethyl 9-(4-cyanophenyl)-7-methyl-6,9-dihydropyrimido[1,2-e]purine-8-carboxylate (20 mg, 55 μmol), 3-(trifluoromethyl)phenylboronic acid (21 mg, 0.11 mmol, 2 eq.), anhydrous copper(II) acetate (20 mg, 0.11 mmol, 2 eq.) and molecular sieve (50 mg, 4 Å) were initially charged. Under an atmosphere of argon, abs. dichloromethane (2 ml), pyridine (18 μl, 0.22 mmol, 4 eq.) and triethylamine (15 μl, 0.11 mmol, 2 eq.) were added. After 12 h of stirring, the mixture was filtered through kieselguhr and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (5.6 mg, 19% of theory).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].CN1CCOCC1.[O:39]1[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:45][CH:42]1[CH2:43][CH2:44][O:39][CH2:40][CH2:41]1)=[O:4]
Reactant: NC1CCOCC1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(NC1CCOCC1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 40 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.07 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (38.2 μL, 0.348 mmol), tetrahydro-2H-pyran-4-amine (12.66 mg, 0.125 mmol), and BOP (55.4 mg, 0.125 mmol). The reaction mixture was stirred overnight and was then purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 50-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow rate=20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)-N-(tetrahydro-2H-pyran-4-yl)acetamide (14.3 mg, 0.028 mmol, 40%): LCMS=515.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.06-8.25 (2 H, m), 7.49-7.78 (7 H, m), 5.04-5.18 (1 H, m), 3.81-4.01 (2 H, m), 3.38-3.58 (2 H, m), 1.73-1.93 (2 H, m), 1.48-1.73 (2 H, m); Analytical LCMS: column: Mac-mod Halo C18, 4.6×50 mm, 2.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 90:10 acetonitrile:water with 10 mM ammonium acetate; Temperature: 45° C.; Gradient: 0-100% B over 4 minutes, flow rate=4 mL/min, product retention=2.6 min.
Reaction SMILES: [CH2:1]=O.[N:3]1([C:9]([S:11][CH3:12])=[S:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:22]=[O:23])[CH:18]=[CH:19][C:20]=1[OH:21]>C(O)C>[CH:22]([C:17]1[CH:16]=[C:15]([O:14][CH3:13])[C:20]([OH:21])=[C:19]([CH:18]=1)[CH2:1][N:6]1[CH2:7][CH2:8][N:3]([C:9]([S:11][CH3:12])=[S:10])[CH2:4][CH2:5]1)=[O:23]
Reactant: CSC(=S)N1CCNCC1
Reactant: C=O
Reactant: COc1cc(C=O)ccc1O
Solvent: CCO
Product: COc1cc(C=O)cc(CN2CCN(C(=S)SC)CC2)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
In 10 ml of ethanol was dissolved 0.86 g of 35% formalin. To the solution was dropwise added under chilling with ice a solution of 1.94 g of methyl 1-piperazinecarbodithioate in 4 ml of ethanol. The mixture was then stirred for 30 min. at room temperature. Under chilling with ice, a solution of 1.52 g of vanilline in 4 ml of ethanol was added to the reaction mixture. The mixture was stirred for 40 min. at room temperature and then refluxed under heating for 10 hours. The reaction mixture was cooled to room temperature to precipitate crystals. The crystals were collected and washed with ethanol to give 2.58 g of the desired compound as a white crystalline product, m.p. 144°-145° C. (decomp.), yield 75.8%.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([B:9]([OH:11])[OH:10])=[CH:5][CH:4]=1)=O.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18]>ClC(Cl)C>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([B:9]([OH:11])[OH:10])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Nc1ccccn1
Solvent: CC(Cl)Cl
Product: OB(O)c1ccc(CNc2ccccn2)cc1
Temperature: 25 °C
Yield: 25.6 %

Procedure:
A mixture of 4-formylphenylboronic acid (1 g, 6.67 mmol) and 2-pyridinylamine (2.51 g, 26.7 mmol) in dichloroethane (25 mL) was stirred under argon at room temperature. To this mixture was added NaB(OAc)3 (1.84 g, 8.67 mmol). The reaction mixture was quenched with H2O after 3 h. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc and washed with water. The organic layer was then dried and concentrated in vacuo. The crude product was then purified by column chromatography (gradient from 20% to 80% EtOAc/hexane) to give product as colorless liquid (0.39 g, 30%). HPLC/MS: (M+H)+ 229.1 m/z. Retention time (LC-MS)=4.54 min. 1H NMR (CD3OD): 7.90 (1H, d); 7.59 (2H, s); 7.43 (1H, m); 7.30(2H, d); 6.55 (2H, m); 4.47 (2H
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O1CCCC1.[N:29]1([CH2:34][CH2:35][CH2:36][NH2:37])[CH:33]=[CH:32][N:31]=[CH:30]1>O>[N:29]1([CH2:34][CH2:35][CH2:36][NH:37][C:9](=[O:11])[CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: NCCCn1ccnc1
Reactant: O=C(O)CCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(CCc1ccccc1)NCCCn1ccnc1
Reaction time: 18 h

Procedure:
A mixture of 1.50 g. of 3-phenylpropionic acid, 1.62 g. of 1,1'-carbonyldiimidazole, and 40 ml. of tetrahydrofuran was stirred for 3 hours and 2.0 g. of 1H-imidazole-1-propanamine was added. The mixture was stirred for 18 hours, 5 ml. of water was added, and the reaction mixture was heated at reflux temperature for 30 minutes. The mixture was concentrated and 10 ml. 1N sodium hydroxide and 100 ml. of methylene chloride were added. The layers were separated and the organic layer was washed with water, dried over magnesium sulfate, and concentrated. The desired product was obtained as an oil, which was converted to the fumarate salt, m.p. 90°-92° C.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:28])[C@@H:13]([OH:27])[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].[C:29](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:28])[C@@H:13]([OH:27])[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]([O:7][CH3:29])=[O:6]
Reactant: O=C([O-])[O-]
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]3C[C@H](O)[C@]12C
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of deoxycholic acid (25.0 g) and anhydrous potassium carbonate (8.8 g) in anhydrous dimethylformamide (65 ml) is added methyl iodide (4.8 ml) and the mixture stirred at room temperature for about 4 hours. The mixture is diluted with ethyl acetate and washed four times with water and once with saturated sodium chloride solution. The organic solution is dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product is purified by flash chromatography in 80% ethyl acetate in hexane to give the desired product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:64]=[CH:63][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([F:62])[CH:57]=2)=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:64]=[CH:63][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([F:62])[CH:57]=2)[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(F)c2)cc1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CCc2cccc(F)c2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 87.1 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 4 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 86 mg (0.3 mmol) (4-tert-butyl-benzyl)-[2-(3-fluoro-phenyl)-ethyl]-amine in 1 ml DMF was added. After stirring for 3 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The orange residue was purified by column chromatography (8 g silica gel; heptane/EtOAc 9:1) to give 112 mg (86%) of a yellow solid. MS (EI) 428.2 (M)+.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH:3]=[CH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.[Cl:18][C:19]1[CH:27]=[C:26]([Cl:28])[C:25]([F:29])=[CH:24][C:20]=1[C:21](Cl)=[O:22]>O1CCOCC1>[CH3:1][N:2]([CH3:10])[CH:3]=[C:4]([C:21](=[O:22])[C:20]1[CH:24]=[C:25]([F:29])[C:26]([Cl:28])=[CH:27][C:19]=1[Cl:18])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C=CN(C)C
Reactant: O=C(Cl)c1cc(F)c(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc(F)c(Cl)cc1Cl
Yield: 83.3 %

Procedure:
14.3 g of ethyl 3-dimethylaminoacrylate and 10.5 g of triethylamine are added dropwise to a solution of 22.75 g of 2,4-dichloro-5-fluorobenzoyl chloride in 100 ml of anhydrous dioxane at 10° to 20° C., with stirring. The mixture is stirred at room temperature for 3 hours, heated at 40°-50° C. for 1 hour, and the solvent is removed by distillation in vacuo and the residue is taken up in methylene chloride/H2O. The phases are separated, and the aqueous solution is again extracted with methylene chloride. The CH2Cl2 solution is washed with water, dried with sodium sulphate, and the solvent is removed in vacuo. The crystalline residue is recrystallized from cyclohexane/light petroleum. 27.8 g of ethyl 3-dimethylamino-2-(2,4-dichloro-5-fluorobenzoyl)acrylate of melting point 94°-95° C. are obtained.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][CH2:13][NH2:14])[C:5]=2[O:4][CH2:3][CH2:2]1.Br[CH2:16][CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1.C(N(CC)CC)C.O>CS(C)=O>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][CH2:13][NH:14][CH2:16][CH2:17][C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: BrCCc1c[nH]c2ccccc12
Reactant: NCCOc1cccc2c1OCCO2
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: c1cc(OCCNCCc2c[nH]c3ccccc23)c2c(c1)OCCO2
Temperature: 90 °C
Reaction time: 14 h

Procedure:
A solution of 2-(2,3-dihydrobenzo[1,4]dioxin-5-yloxy) ethylamine (0.38 g, 1.9 mmol), 3-(2-bromoethyl)-indole (0.24 g, 1.1 mmol) and triethylamine (0.22 g, 2.2 mmol) in anhydrous dimethylsulfoxide (20 ml) was allowed to stir for 14 hours at 90° C. The mixture was poured into water (100 ml) and extracted with methylene chloride (3×100 ml). The organic layer was washed with water (3×150 ml), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. Chromatography (10% methanol-methylene choride plus ammonium hydroxide) afforded 0.19 g (52%) as a yellow oil.