Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[S:13]([N:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][CH:4]=1.S(Cl)([Cl:25])(=O)=O>C(O)(=O)C>[Cl:25][C:4]1[CH:5]=[C:6]([C:19]([OH:21])=[O:20])[C:7]2[C:12]([C:3]=1[O:2][CH3:1])=[C:11]([S:13]([N:16]([CH3:17])[CH3:18])(=[O:15])=[O:14])[CH:10]=[CH:9][CH:8]=2
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1ccc(C(=O)O)c2cccc(S(=O)(=O)N(C)C)c12
Solvent: CC(=O)O
Product: COc1c(Cl)cc(C(=O)O)c2cccc(S(=O)(=O)N(C)C)c12
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
4-Methoxy-5-(dimethylaminosulfonyl)-1-naphthalenecarboxylic acid (15.26 g, 50 mmoles), described in Example 1a) was suspended in acetic acid (46 ml). Sulfuryl chloride (6 ml, 75 mmoles) was added portionwise to the suspension at such a rate that the temperature did not exceed 32° C. The resulting solution was stirred at 20°-22° C. for 2 hr and then poured into 460 ml of ice water. The mixture was stirred for 30 min. The precipitate was collected and dried over P2O5 to give 16.7 g of the title compound; mp 127°-137° C.; NMR (CDCl3) δ 3.05 (s, 6H), 4.12 (s, 3H), 8.0 (broad, 1H), 7.7 and 9.25 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[CH:11]=[O:12].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O>>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[CH:11]=[O:12]
Reactant: O=Cc1c(Br)ccc2c1OCO2
Reactant: OB(O)c1ccccc1F
Product: O=Cc1c(-c2ccccc2F)ccc2c1OCO2

Procedure:
The process described in Method B was followed. 5-Bromo-1,3-benzodioxole-4-carbaldehyde (0.458 g, 2.00 mmol) and 2-fluorophenylboronic acid (0.420 g, 3.00 mmol) were used to obtain the title compound. The crude product was purified by column chromatography with a mixture of hexane:ethyl acetate (4:1) as the eluent.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH:8]=[C:9](C(O)=O)[S:10][C:6]=2[C:5]([O:14][CH3:15])=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1>CC(N(C)C)=O>[F:1][C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[C:5]([O:14][CH3:15])=[CH:4][CH:3]=1
Reactant: COc1ccc(F)c2cc(C(=O)O)sc12
Solvent: CC(=O)N(C)C
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(F)c2ccsc12
Temperature: 200 °C
Yield: 69.5 %

Procedure:
4-Fluoro-7-methoxy-1-benzothiophene-2-carboxylic acid (2.00 g, 8.84 mmol) was added in one portion to DBU (8 mL) and dimethyl acetamide (10 mL). This was heated in the microwave with 300 W at 200° C. for 1 h. The reaction mixture was allowed to cool and poured onto water (100 mL). Product was extracted with hexane (2×100 mL), washed with aqueous hydrochloric acid (2 N, 50 mL), aqueous sodium hydroxide (2 N, 50 mL), and the combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography eluting silica gel with hexane:ethyl acetate [96:4] to give an oil (1.12 g, 70%): δH (300 MHz, CDCl3) 7.4 (2H, s, Ar), 6.9 (1H, t, Ar), 6.60 (1H, dd, Ar), 3.91 (3H, s, OCH3).
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:15]([NH:17][C@H:18]([C:31]([OH:33])=[O:32])[CH2:19][CH2:20][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>N1CCCCC1.O1CCOCC1>[NH2:1][C@H:2]([C:15]([NH:17][C@H:18]([C:31]([OH:33])=[O:32])[CH2:19][CH2:20][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Solvent: C1COCCO1
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Fmoc-L-Lys(Boc)-L-Glu(OBzl)-OH (69.0 g, 0.1 mol) was dissolved in 300 ml of 20% piperidine in dioxane and stirred for 1 hour at room temperature. The solvent was evaporated in vacuum and residual oil was dissolved in 0.1% AcOH. The precipitate was filtered off and washed with 0.1% AcOH and water to neutral pH. The yield was 43.7 (94%). Rf=0.5 (CHCl3:MeOH: 32% AcOH=5:3:1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH3:23])[CH2:14][CH2:13][S:12][C:11]([NH:15]C(=O)OC(C)(C)C)=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].FC(F)(F)C(O)=O>CO>[Br:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH3:23])[CH2:14][CH2:13][S:12][C:11]([NH2:15])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2ccc(F)c(Br)c2)CCS1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: C[C@@]1(c2ccc(F)c(Br)c2)CCSC(N)=N1
Temperature: 60 °C
Reaction time: 15 h
Yield: 62 %

Procedure:
To a solution of (S)-tert-butyl 4-(3-bromo-4-fluorophenyl)-4-methyl-5,6-dihydro-4H-1,3-thiazin-2-ylcarbamate (1.1 g, 2.7 mmoles) and methanol (10 mL) is added trifluoroacetic acid (10 mL). The reaction mixture is warmed to 60° C. After 15 h, the solvent is removed under reduced pressure. Water is added to the resulting residue and the mixture is made basic with saturated sodium bicarbonate. The basic aqueous phase is extracted with dichloromethane. The organic phase is separated, dried over sodium sulfate, filtered, and the solvent removed under reduced pressure to give the title compound (62% yield): MS (m/z): 303, 305 (M+1).
Reaction SMILES: Cl[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[OH:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O>[NH2:4][C:3]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:2]=1[S:19][C:16]1[CH:17]=[CH:18][C:13]([OH:12])=[CH:14][CH:15]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1cc([N+](=O)[O-])ccc1Sc1ccc(O)cc1
Temperature: 0 °C
Yield: 46 %

Procedure:
A solution of 2-Chloro-5-nitroaniline (3 g, 17.4 mmole), 4-hydroxythiophenol (2.4 g, 19.0 mmol), cesium carbonate (12.35 g, 38 mmol) in dimethylformamide (35 ml) was heated at 100° C. for 16 hours. Afterwards ice water (200 mL) was added to the solution and to the resultant slurry was added ethyl acetate (200 ml). The layers were separated and the organic layer was washed with 10% sodium bicarbonate and 10% sodium chloride, dried over anhydrous sodium sulfate. The drying agent was filtered and solvent was removed under vacuum leaving a yellow oil. The oil was purified by silica gel chromatography eluting with methylene chloride/methanol (97:3), to provide a yellow solid as the title compound (2.1 g, 46%).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:16])([CH3:15])[C:4](=[O:14])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[Br:17]Br>C(Cl)(Cl)(Cl)Cl>[Br:17][CH:5]([O:6][C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1)[C:4](=[O:14])[C:3]([CH3:16])([CH3:15])[CH2:2][Cl:1]
Reactant: BrBr
Reactant: CC(C)(CCl)C(=O)COc1ccc(Cl)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(CCl)C(=O)C(Br)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7890.2 %

Procedure:
210 g (0.81 mol) of 4-chloro-1-(4-chlorophenoxy)-3,3-dimethyl-butan-2-one were dissolved in 1,000 ml of carbon tetrachloride. 41 ml (0.01 mol) of bromine were added dropwise at room temperature at a rate such that it was continuously consumed. The mixture was then stirred at room temperature for 30 minutes. After distilling off the solvent in vacuo, 268.3 g (98% of theory) of crude 1-bromo-4-chloro-1-(4-chlorophenoxy)-3,3-dimethyl-butan-2-one were obtained and were further reacted directly. ##STR13##
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:20][S:21][CH2:22][C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)[C:10]([S:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)=[C:9]([OH:18])[C:8](=[O:19])[O:7]1)=[O:5])[CH3:2].N1C=CC=CC=1.[CH3:34][C:35]([CH3:40])([CH3:39])[C:36](Cl)=[O:37]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([CH2:20][S:21][CH2:22][C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)[C:10]([S:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)=[C:9]([O:18][C:36](=[O:37])[C:35]([CH3:40])([CH3:39])[CH3:34])[C:8](=[O:19])[O:7]1)=[O:5])[CH3:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCOC(=O)C1(CSCc2ccco2)OC(=O)C(O)=C1SCc1ccco1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1(CSCc2ccco2)OC(=O)C(OC(=O)C(C)(C)C)=C1SCc1ccco1
Reaction time: 8 h
Yield: 88.1 %

Procedure:
To a solution of 4-hydroxy-5-oxo-3-(2-furanylmethylsulfanyl)-2-[(2-furanylmethylsulfanyl)-methyl]-2,5-dihydrofuran-2-carboxylic acid ethyl ester (0.3 g, 0.73 mmol) in methylene chloride (25 mL) were added pyridine (0.19 mL, 2.36 mmol) and trimethylacetyl chloride (0.22 mL, 1.77 mmol, 2.4 eq) under argon atmosphere. The mixture was gently refluxed overnight under argon and then evaporated. The residue was purified by column chromatography eluted with a mixed solvent of hexane and ethyl acetate (4:1, v/v) affording 0.3181 g of 4-(2,2-dimethyl-propionyloxy)-3-(furan-2-ylmethylsulfanyl)-2-(furan-2-ylmethylsulfanylmethyl)-5-oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester as light yellow oil. 1H NMR (CDCl3, 300.16 MHz) δ (ppm): 7.40-7.37 (m, 2H), 6.35-6.25 (m, 4H), 4.35 (s, 2H), 4.33-4.22 (m, 2H), 3.90 (d, J=14.7 Hz, 1H), 3.80 (d, J=14.7 Hz, 1H), 3.29 (d, J=15.1 Hz, 1H), 2.97 (d, J=15.1 Hz, 1H), 1.37 (s, 9H) and 1.29 (t, J=7.1 Hz, 3H). 13C NMR (CDCl3, 75.48 MHz) δ (ppm): 174.35, 166.32, 163.84, 150.29, 148.27, 144.72, 143.10, 142.64, 136.15, 111.00, 110.47, 109.44, 108.98, 87.64, 63.40, 39.30, 36.15, 29.62, 28.02, 26.99 and 14.04. MS (ESI, rel. int.) m/z: 495 (M+H+, 25), 517 (M+Na+, 100).
Reaction SMILES: Br[C:2]1[CH:32]=[C:31]([F:33])[C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]3[N:21]=[C:20]([NH:22][C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)[C:19]([O:29][CH3:30])=[CH:18][N:17]=3)=[N:8]2)=[C:4]([F:34])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:40]([O:42][CH2:43][CH3:44])=[CH2:41])CCC.CN1CCCC1=O>C1(C)C=CC=CC=1.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:43]([O:42][C:40]([C:2]1[CH:3]=[C:4]([F:34])[C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]3[N:21]=[C:20]([NH:22][C:23]4[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=4)[C:19]([O:29][CH3:30])=[CH:18][N:17]=3)=[N:8]2)=[C:31]([F:33])[CH:32]=1)=[CH2:41])[CH3:44]
Reactant: COc1cnc(-c2nn(Cc3c(F)cc(Br)cc3F)c3ccccc23)nc1Nc1ccncc1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Product: C=C(OCC)c1cc(F)c(Cn2nc(-c3ncc(OC)c(Nc4ccncc4)n3)c3ccccc32)c(F)c1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
100 mg of 2-[1-(4-bromo-2,6-difluorobenzyl)-1H-indazol-3-yl]-5-methoxy-N-(pyridin-4-yl)pyrimidin-4-amine (2-12-1, 0.191 mmol, 1 eq.) was suspended in dry toluol. 1.34 mg of dichloropalladium-triphenylphosphane (1:2) (0.002 mmol, 0.01 eq.) and 71 μl of tributyl(1-ethoxyethenyl)stannane (0.21 mmol, 1.2 eq.) were added. The mixture was stirred for 5 hours at 100° C. bath temperature and for 18 hours at 120° C. bath temperature. 5 mg of dichloropalladium-triphenylphosphane (1:2) (0.007 mmol, 0.035 eq.) and 140 μl of tributyl(1-ethoxyethenyl)stannane (0.42 mmol, 2.4 eq.) and 1 ml of 1-methylpyrrolidin-2-one were added. The solution was stirred for 3 days at 100° C. bath temperature. 5 mg of dichloropalladium-triphenylphosphane (1:2) (0.007 mmol, 0.035 eq.) and 140 μl of tributyl(1-ethoxyethenyl)stannane (0.42 mmol, 2.4 eq.) were added and stirred at 100° C. again for 22 hours. The reaction mixture was concentrated in vacuo and purified by flash chromatography to yield 119 mg (0.2 mmol, 107%) of the analytically pure target compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH2:5]2.[CH:13]1([CH2:18][C:19]2[O:23][N:22]=[C:21]([NH:24][C:25](=[O:31])[C@@H:26]([NH2:30])[CH2:27][CH2:28][CH3:29])[CH:20]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[CH:13]1([CH2:18][C:19]2[O:23][N:22]=[C:21]([NH:24][C:25](=[O:31])[C@@H:26]([NH:30][CH:7]3[CH2:6][CH2:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=4)[CH2:8]3)[CH2:27][CH2:28][CH3:29])[CH:20]=2)[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CCC[C@H](N)C(=O)Nc1cc(CC2CCCC2)on1
Reactant: O=C1CCc2cc(F)ccc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCC[C@H](NC1CCc2cc(F)ccc2C1)C(=O)Nc1cc(CC2CCCC2)on1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-Fluoro-3,4-dihydro-1H-naphthalen-2-one (0.2 mmol) was combined with 2-(S)-Amino-pentanoic acid (5-Cyclopentylmethyl-isoxazol-3-yl)-amide (0.2 mmol) in 2 mL of anhydrous dichloromethane under N2. Sodium triacetoxyborohydride (0.3 mmol) and two drops acetic acid were added and the reaction was stirred at rt for 16 h. The crude solution was then concentrated under reduced pressure and purified through flash chromatography on silica gel to give 2-(S)-(6-Fluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid (5-cyclopentylmethyl-isoxazol-3-yl)-amide, LC-MS: retention time 2.0 min, M+1: 414.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C@H:6]([N:13]1[C:17]([CH2:18]O)=[CH:16][NH:15][C:14]1=[S:20])[CH2:7]2.S(Cl)(Cl)=O.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>CN(C=O)C>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C@H:6]([N:13]1[C:17]([CH2:18][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:16][NH:15][C:14]1=[S:20])[CH2:7]2
Reactant: C1CCNC1
Reactant: OCc1c[nH]c(=S)n1[C@H]1CCc2c(F)cc(F)cc2C1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Fc1cc(F)c2c(c1)C[C@@H](n1c(CN3CCCC3)c[nH]c1=S)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
A solution of (S)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-5-hydroxymethyl-1,3-dihydroimidazole-2-thione (140 mg, 0.47 mmol), prepared as in Example 18, in 20 mL of THP and 1 drop of DMF was cooled to between 0° and 5° C. and thionyl chloride (13.7M, 109 μL, 1.49 mmol) was added drop-wise under a nitrogen atmosphere. The mixture was stirred at room temperature for 0.5 hours, under reflux for 0.5 hours and again at room temperature for 0.5 hours. The mixture then was cooled to between 0° and 5° C. and pyrrolidine (12.0M, 818 μL, 9.8 mmol) was added drop-wise. The mixture was stirred under reflux for 1.5 hours. The solvents were removed by evaporation and the residue was diluted with water. Ethyl acetate was added to the dilution and the mixture was adjusted to pH 7. The ethyl acetate layer was dried and concentrated by evaporation. Purification of the residue by column chromatography gave (S)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydro-5-(pyrrolidin-1-ylmethyl)-imidazole-2-thione (100 mg, 0.29 mmol). [α]D25 =-10.96° (c=1.3, DMSO).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([CH2:14][N:15]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:3]=1.[CH:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]([CH3:35])[CH3:34])[C:28]=1[N:36]=[C:37]=[O:38])([CH3:26])[CH3:25]>C(#N)C>[CH3:26][CH:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]([CH3:34])[CH3:35])[C:28]=1[NH:36][C:37]([NH:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([CH2:14][N:15]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:3]=1)=[O:38])[CH3:25]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCCCN(CCCC)Cc1cc(N)n(Cc2ccccc2)n1
Solvent: CC#N
Product: CCCCN(CCCC)Cc1cc(NC(=O)Nc2c(C(C)C)cccc2C(C)C)n(Cc2ccccc2)n1
Temperature: 25 °C
Yield: 35.1 %

Procedure:
A solution of 5-amino-3-[(dibutylamino)methyl]-1-(phenylmethyl)-1H-pyrazole (0.70 g, 2.2 mmol), 2,6-diisopropylphenylisocyanate (0.48 mL, 2.2 mmol), and cuprous iodide (cat) in acetonitrile was heated to reflux for 16 hours. The resulting solution was cooled (25° C.), concentrated in vacuo, and chromatographed on silica (90:10 hexane:ethyl acetate). The product containing fractions were combined and concentrated in vacuo. The resulting oil was crystallized from hexane to yield 0.40 g (34.7%) of the title compound as a white powder, m.p. 149°-151.5° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:10]1[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:17].C(N(CC)CC)C>CCOCC>[C:1]([O:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:17])[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cccc(O)c1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1cccc(OC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 212 %

Procedure:
A solution of benzoyl chloride (32.5 g, Aldrich) in ether (200 ml) was added dropwise to a stirred solution of m-cresol (25.0 g, Aldrich) and triethylamine (27.2 g, Aldrich) in ether (500 ml). The reaction mixture was stirred at room temperature for 1 hour then filtered. The ethereal filtrate was washed with saturated NaHCO3 and water then dried over Na2SO4. The ether layer was separated, dried and concentrated in vacuo to give the desired product (104.0 g) as a white solid, mp 45-47C. 1H NMR consistent with the desired structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]2[CH2:18][CH2:19][C:20](O)=[O:21].N1C=CC=CC=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>C(Cl)Cl>[C:29]([N:8]1[C:9]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]3[C:20](=[O:21])[CH2:19][CH2:18][CH:6]([C:5]=23)[CH:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:31])[CH3:30]
Reactant: COc1ccc2c(c1)C(CCC(=O)O)C(c1ccccc1)N2
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc2c3c1C(=O)CCC3C(c1ccccc1)N2C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
5-methoxy-2-phenyl-2,3-dihydroindole-3-propionic acid (10.2 g) synthesized as in Example 1, steps 1 and 2, was dissolved in anhydrous methylene chloride (80 ml). Pyridine (2.77 ml), then acetic anhydride (3.24 ml) were added to the solution under cooling with ice, and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was poured into ice water. The organic layer of the mixture was separated, washed with 1N hydrochloric acid, water and saturated aqueous solution of sodium chloride successively and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure to yield 11.5 g (99%) of the titled compound as a crude rubber-like product.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:10]1[CH:11]=[C:12]([N:17]2[C:21](=[O:22])[O:20][N:19]=[C:18]2[C:23]2[C:24]([NH:28][C:29](=O)[C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)=[N:25][O:26][N:27]=2)[CH:13]=[CH:14][C:15]=1[F:16])#[N:9].P(Cl)(Cl)(Cl)(Cl)Cl.C([BH3-])#N.[Na+]>N1C=CC=CC=1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:16][C:15]1[CH:14]=[CH:13][C:12]([N:17]2[C:21](=[O:22])[O:20][N:19]=[C:18]2[C:23]2[C:24]([NH:28][CH2:29][C:30]3[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=3)=[N:25][O:26][N:27]=2)=[CH:11][C:10]=1[C:8]#[N:9]
Reactant: N#Cc1cc(-n2c(-c3nonc3NC(=O)c3ccncc3)noc2=O)ccc1F
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(-n2c(-c3nonc3NCc3ccncc3)noc2=O)ccc1F
Reaction time: 3 h

Procedure:
A solution of N-{4-[4-(3-cyano-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}isonicotinamide trifluoroacetate (37 mg, 72 μmol) in pyridine (1.5 mL) at 0° C. was treated with phosphorus pentachloride (45 mg, 0.22 mmol) and stirred for 3 h. The reaction mixture was concentrated, diluted with ethanol (2.5 mL), treated with sodium cyanoborohydride (14 mg, 0.22 mmol), and stirred for 16 h. The reaction mixture was purified by preparative LCMS to give the intermediate 2-fluoro-5-[5-oxo-3-{4-[(pyridin-4-ylmethyl)amino]-1,2,5-oxadiazol-3-yl}-1,2,4-oxadiazol-4(5H)-yl]benzonitrile trifluoroacetate. This material was diluted with ethanol (1 mL), treated with 2.0 M sodium hydroxide in water (0.2 mL), and stirred for 45 min. Purification of the crude reaction mixture by preparative HPLC gave the desired product (8 mg, 24%). LCMS for C16H13FN7O2 (M+H)+: m/z=354.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[F:18])[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>O1CCCC1>[F:18][C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:27]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:28])[CH:7]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
2-Amino-4-(2-fluoro-4-nitrophenoxy)pyridine (2.71 g) was dissolved in tetrahydrofuran (60 ml) under a nitrogen atmosphere, and then triethylamine (2.27 ml) and phenyl chloroformate (2.05 ml) were added dropwise thereto while cooling in an ice water bath, followed by stirring at room temperature for 25 min. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to provide a crude product of 4-(2-fluoro-4-nitrophenoxy)-2-(phenoxycarbonylamino)pyridine (5.00 g). The crude product was dissolved in tetrahydrofuran (50 ml), and then pyrrolidine (3.64 ml) was added at room temperature, followed by stirring for 1 hr. To the reaction mixture was added a saturated aqueous solution of ammonium chloride, followed by extracting with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and an brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:2 to 1:4, then ethyl acetate) to provide the titled compound (2.927 g, 78%) as pale brown crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:44])([CH3:43])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH2:40][NH2:41])=[CH:30][CH:29]=2)[C:17]1=[O:42])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C([O-])=O.[CH2:52]([N:55]=[C:56]=[O:57])[CH2:53][CH3:54]>>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:44])([CH3:43])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH2:40][NH:41][C:56]([NH:55][CH2:52][CH2:53][CH3:54])=[O:57])=[CH:32][CH:33]=2)[C:17]1=[O:42])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCN=C=O
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CN)cc2)C1=O
Agent: O=C([O-])C(F)(F)F
Product: CCCNC(=O)NCc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)C(C)(C)NC(=O)OCc3ccccc3)CCc3ccccc32)cc1

Procedure:
Prepared from 2-benzyloxycarbonylamino-2-methyl- N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(aminomethyl) [1,1'-biphenyl]-4-yl]methyl]-1H-benzazepin-3(R)-yl]propanamide, trifluoroacetate (Example 36, Step A) and 1-propyl isocyanate according to the procedure described in Example 37, Step A. 1H NMR (200 MHz, CD3OD): δ 0.86 (t, 7.5 Hz, 3H), 1.39 (s, 6H), 1.42 (m, 2H), 1.82 (m, 1H), 2.19-2.55 (m, 3H), 3.01 (t, 7 Hz, 2H), 4.12 (s, 2H), 4.32 (m, 1H), 4.85 (d, 15 Hz, 1H), 5.00 (s, 2H), 5.31 (d, 15 Hz, 1H), 7.08-7.40 (m, 17H), 7.63 (d, 8 Hz, 1H). FAB-MS: calculated for C40H45 N5O5 675; found 676 (M+H, 85%).