Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C@H:13]([O:19][CH3:20])[C@@H:14]([CH3:18])[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl.[CH3:31][O:32][C:33](=[O:43])[C@H:34]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[NH2:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C@H:13]([O:19][CH3:20])[C@@H:14]([CH3:18])[C:15]([NH:35][C@H:34]([C:33]([O:32][CH3:31])=[O:43])[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:17])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: CO[C@H]([C@@H](C)C(=O)O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)[C@@H](OC)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 65.5 %

Procedure:
To a mixture of #11 (2.7 g, 9.4 mmol, 1 eq.) in dichloromethane (30 mL, 0.3 M) and N,N-dimethylformamide (3 mL) were added diisopropylethylamine (3.30 mL, 18.8 mmol, 2 eq.), L-phenylalanine methyl ester hydrochloride (2.03 g, 9.40 mmol, 1.2 eq.) and HATU (4.79 g, 12.2 mmol, 1.3 eq.). The reaction was stirred for 18 hours and then concentrated in vacuo. The residue was taken up in ethyl acetate (100 mL) and washed sequentially with 1 M hydrochloric acid (2×50 mL) and brine. The organic layer was dried over sodium sulfate, filtered and evaporated in vacuo. The crude material was taken up in dichloromethane and filtered. The filtrate was purified by silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) to give #37 (2.76 g, 65%) as an off-white solid. LC-MS: m/z 449.3 [M+H+], 349.2 [(M−Boc)+H+] retention time=0.88 minutes; 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ 8.28 (d, J=8.2 Hz, 1H), 7.14-7.29 (m, 5H), 4.50 (ddd, J=10.9, 8.1, 4.4 Hz, 1H), 3.64 (s, 3H), 3.23 (s, 3H), 2.15-2.24 (m, 1H), 1.56-1.76 (m, 2H), 1.31-1.55 (m, 11H), 1.02 (d, J=6.6 Hz, 3H).
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].[CH:25]1([C:31](O)=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][N:11]2[C:31]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:32])=[O:9])[CH2:6][CH2:5]1)#[N:3]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Reactant: O=C(O)C1CCCCC1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C(=O)C2CCCCC2)CC1

Procedure:
(2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K4 was coupled with cyclohexanecarboxylic acid in analogy to experiment A1 to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-cyclohexanecarbonyl-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a colorless oil. MS: 464.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[C:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].CC[N:27](CC)CC.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>C(Cl)Cl.C(Cl)Cl.CO>[C:15]([O:14][C:12]([N:19]1[CH2:20][CH2:21][N:22]([CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=2)[C:9]([NH2:27])=[O:11])[CH2:23][CH2:24]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCN(CC)CC
Reactant: O=C(O)Cc1cccc(O)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(C(N)=O)c2cccc(O)c2)CC1

Procedure:
3-Hydroxyphenylacetic acid (0.50 g, 3.3 mmol), BOC piperazine (0.737 g, 3.96 mmol), Et3N (0.92 mL, 6.6 mmol), and CH2Cl2 (7 mL) were combined, cooled to 4° and solid Bis(2-oxo-3-oxazolidinyl)-phosphinic chloride (0.840 g, 3.3 mmol)was added under Ar. The ice bath was removed and a clear solution was obtained on warming to 23°. After 1 hour tlc (silica plates, 19:1 CH2Cl2/CH3OH) indicated a completed reaction. The reaction was diluted with CH2Cl2(100 mL), washed with 0.3 N HCl (20 mL), H2O (20 mL), satd aq NaHCO3 (20 mL) and Satd aq NaCl (20 mL), dried (Na2SO4) filtered and the filtrate was diluted with CH3OH til ca 4% CH3OH in CH2Cl2 and filtered through a pad of silica to afford the title compound as a white foam. 1H NMR (CDCl3): d 7.13 (m, 1), 6.81 (s, 1), 6.73 (d, 1), 6.68 (d, 1), 3.69 (s, 2), 3.59 (m,2), 3.39 (m, 4), 3.22 (m, 2), 1.46 (s, 9).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[NH2:10])[CH3:2].C[Al](C)C.CO[C:17](=O)[CH2:18][N:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:24]1[N:29]=[CH:28][CH:27]=[CH:26][N:25]=1>ClC(Cl)C.C1(C)C=CC=CC=1>[CH2:1]([N:3]1[C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=[C:17]1[CH2:18][N:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:24]1[N:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[CH3:2]
Reactant: CCNc1ccncc1N
Reactant: COC(=O)Cn1ccnc1-c1ncccn1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CC(Cl)Cl
Product: CCn1c(Cn2ccnc2-c2ncccn2)nc2cnccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.1 %

Procedure:
To a solution of N4-ethyl-pyridine-3,4-diamine (Justus Liebigs Ann. Chem. (1935) 518, 274, 287) (125 mg, 0.9 mmol) in dichloroethane (10 mL) is added a solution of AlMe3 in toluene (2M, 1.37 mL) dropwise under nitrogen. After addition, the mixture is stirred at room temperature for one hour and (2-pyrimidin-2-yl-imidazol-1-yl)-acetic acid methyl ester (100 mg, 0.45 mmol) is added in one portion. The reaction mixture is heated with stirring at 80° C. for 2 days. After cooled, the mixture is quenched with 5 mL of water, 2 drops of 5 N NaOH and extracted with CH2Cl2 (10 mL×5). The combined organic extracts are dried over Na2SO4, and concentrated. The residue is dissolved in 10 mL of acetic acid and the resulting mixture is heated at 100° C. overnight. After removal of acetic acid under vacuum, the residue is basified with saturated NaHCO3 solution and extracted with CH2Cl2 (10 mL×5). The combined organic extracts are dried over Na2SO4, and concentrated. The residue is purified on a silica gel column with 10:1 CH2Cl2/MeOH as eluent to yield the title compound (40 mg). 1H NMR (CDCl3) δ: 9.09 (s, 1H), 8.85 (d, 2H), 8.46 (d, 1H), 7.26-7.30 (m, 3H), 7.16 (1H), 6.39 (s, 2H), 4.25 (q, 2H), 1.15 (t, 3H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].Cl[C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:9]=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:7]=1.[C:28]1([CH:35]=[CH:34][CH:33]=[C:31]([OH:32])[CH:30]=1)[OH:29].Cl>C1(C)C=CC=CC=1>[OH:29][C:28]1[CH:30]=[C:31]([OH:32])[CH:33]=[CH:34][C:35]=1[C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:9]=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:7]=1
Reactant: COc1ccc(-c2nc(Cl)nc(-c3ccc(OC)cc3)n2)cc1
Reactant: Oc1cccc(O)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nc(-c3ccc(OC)cc3)nc(-c3ccc(O)cc3O)n2)cc1
Reaction time: 6 h

Procedure:
10.3 g (0.077 mol) of aluminium chloride are added at 5 C. to a mixture of 23.0 g (0.07 mol) of 2-chloro-4,6-bis(4-methoxyphenyl)-1,3,5-triazine of the formula (108a) and 8.5 g (0.077 mol) of resorcinol in 150 ml of toluene. The temperature is allowed to rise to 20 C., and the mixture is then heated at 50 C. for 6 hours and at reflux for 24 hours. The cooled mixture is poured into 150 ml of 12% hydrogen chloride solution, and the crude product is filtered, washed neutral with water and then washed with methanol and dried to give a dark yellow product of the formula ##STR22##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.[O:27]1[CH2:31][CH2:30][CH:29]([CH:32]=[O:33])[CH2:28]1.[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH:32]([OH:33])[CH:29]3[CH2:30][CH2:31][O:27][CH2:28]3)[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: O=CC1CCOC1
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cn(C(C(=O)OC(C)(C)C)C(O)C2CCOC2)c(=O)cc1-c1cc(Cl)ccc1C#N
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
At −70° C., 6.94 ml (6.94 mmol, 1.3 eq.) of bis(trimethylsilyl)lithium amide (1M in THF) were added dropwise to a solution of 2.00 g (5.34 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in 50 ml of tetrahydrofuran, the mixture was stirred at −70° C. for 10 min, a solution of 801 mg (8.00 mmol, 1.5 eq.) of tetrahydrofuran-3-carbaldehyde in 4 ml of tetrahydrofuran was added and the mixture was stirred at −70° C. for 90 min. The reaction mixture was warmed to −20° C., and 25 ml of semisaturated aqueous ammonium chloride solution were added. After phase separation, the aqueous phase was extracted with diethyl ether. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried (sodium sulphate), filtered, concentrated under reduced pressure and dried. The crude product was purified by flash chromatography (KP-SIL, petroleum ether/ethyl acetate 33-75%). Yield: 1.49 g (56% of theory)
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[N:6][N:5]=[C:4]1[S:13][CH3:14])[CH3:2].OO.[OH-:17].[Na+].C(O)(=[O:21])C>>[CH2:1]([N:3]1[C:7]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[N:6][N:5]=[C:4]1[S:13]([CH3:14])(=[O:21])=[O:17])[CH3:2]
Reactant: [OH-]
Reactant: CC(=O)O
Reactant: CCn1c(SC)nnc1-c1cccs1
Agent: OO
Agent: [Na+]
Product: CCn1c(-c2cccs2)nnc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
The title compound was synthesized according to the method described in Åkerblom et al. J. Med. Chem. 16, 312 (1973). 4-Ethyl-3-methylsulfanyl-5-thiophen-2-yl-4H-[1,2,4]triazole (1.14 g, 5.06 mmol) was dissolved in glacial acetic acid (20 ml) followed by the addition of 30% hydrogen peroxide (5 ml). After stirring at ambient temperatures for 16 h additional 30% hydrogen peroxide (5 ml) was added. The mixture was stirred for 3 h at ambient temperature, then heated to 100° C. for 2.5 h. After cooling in an ice/water bath the reaction was neutralized with sodium hydroxide and extracted twice with dichloromethane. The organic layers were combined, evaporated to dryness and dried in vacuo yielding the title compound (0.78 g, 60%). 1H NMR (CDCl3), δ (ppm): 7.60 (d, 1H), 7.56 (d, 1H), 7.22 (m, 1H), 4.51 (q, 2H), 3.58 (s, 3H), 1.55 (t, 3H).
Reaction SMILES: OC(C(F)(F)F)=O.Br[C:9]1[CH:10]=[C:11]2[C:18]3([O:22][N:21]([CH3:23])[C:20](=[NH:24])[NH:19]3)[CH2:17][CH:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:15][C:12]2=[CH:13][CH:14]=1.[C:31]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)#[N:32].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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>[NH2:24][C:20]1[N:21]([CH3:23])[O:22][C:18]2([C:11]3[C:12](=[CH:13][CH:14]=[C:9]([C:37]4[CH:38]=[C:33]([CH:34]=[CH:35][CH:36]=4)[C:31]#[N:32])[CH:10]=3)[O:15][CH:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:17]2)[N:19]=1
Reactant: CN1OC2(CC(c3ccccc3)Oc3ccc(Br)cc32)NC1=N
Reactant: N#Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: O
Product: CN1OC2(CC(c3ccccc3)Oc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Temperature: 100 °C
Yield: 27.4 %

Procedure:
To a solution of 6-bromo-2′-methyl-2-phenylspiro[chroman-4,5′-[1,2,4]oxadiazolidin]-3′-imine TFA salt (45 mg, 0.092 mmol), 3-cyanophenylboronic acid (20 mg, 0.14 mmol) and Cs2CO3 (60 mg, 0.18 mmol) in 1,4-dioxane (3 mL) and H2O (0.5 mL) in a 10 mL CEM microwave test tube was added PdCl2(PPh3)2 (10 mg). After degassing by purging with N2, the mixture was heated to 100° C. for 5 min in a CEM microwave reactor. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give 3-(3′-amino-2′-methyl-2-phenyl-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazole]-6-yl)benzonitrile (10 mg) as a TFA salt. MS ESI +ve m/z 397 (M+H)+. 1H-NMR (400 MHz, DMSO-d6): 8.14-8.12 (m, 2H), 8.03 (d, J=8.4 Hz, 1H), 7.84-7,79 (m, 2H), 7.66 (t, J=8.0 Hz, 1H), 7.54-7.40 (m, 5H), 7.09 (d, J=8.8 Hz, 1H), 5.29 (d, 11.6 Hz, 1H), 3.34 (s, 3H), 2.75 (d, 14.0 Hz, 1H), 2.37 (dd, J=14.4, 13.2 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH2:30][C:31]1[CH:39]=[CH:38][C:34]([CH2:35][CH2:36][OH:37])=[CH:33][CH:32]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:30][C:31]2[CH:39]=[CH:38][C:34]([CH2:35][CH2:36][OH:37])=[CH:33][CH:32]=2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: Nc1ccc(CCO)cc1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CNc3ccc(CCO)cc3)ccc21
Yield: 99.9 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (30.0 mg, 0.0730 mmol) was dissolved in acetonitrile (2 mL), and the solution was treated with 4-aminophenethyl alcohol (40 mg, 0.29 mmol), acetic acid (0.084 mL, 1.5 mmol) and sodium triacetoxyborohydride (46 mg, 0.22 mmol). The reaction mixture was added with 1 mol/L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, followed by drying over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain Compound 4-chloro-7-{1-(tert-butoxycarbonyl)-5-[4-(2-hydroxyethyl)phenylaminomethyl]indol-2-yl}isoindolinone (38.8 mg, yield 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14](=[O:15])[N:13]([CH3:16])[C:12](=[O:17])[N:11]([CH2:18][C:19]([O:21]C(C)C)=[O:20])[C:10]1=[O:25].[N+:26]([O-])([OH:28])=[O:27]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:26]([O-:28])=[O:27])=[CH:4][C:3]=1[N:9]1[C:14](=[O:15])[N:13]([CH3:16])[C:12](=[O:17])[N:11]([CH2:18][C:19]([OH:21])=[O:20])[C:10]1=[O:25]
Reactant: CC(C)OC(=O)Cn1c(=O)n(C)c(=O)n(-c2ccc(F)cc2Cl)c1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cn1c(=O)n(CC(=O)O)c(=O)n(-c2cc([N+](=O)[O-])c(F)cc2Cl)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of isopropyl 3-(2-chloro-4-fluorophenyl)-tetrahydro-5-methyl-2,4,6-trioxo-s-triazine-1(2H)-acetate (48.7 g, 0.0508 mol) in concentrated sulfuric acid is cooled to 0° C., treated with 90% nitric acid (2.6 mL), stirred at room temperature overnight, treated with 90% nitric acid (1.0 mL), stirred for 4 hours, treated with 90% nitric acid (2.0 ml) stirred at room temperature overnight, treated with 90% nitric acid (1.0 mL), stirred for 1 hour and poured onto ice. The resultant aqueous solution is filtered to obtain a solid. A solution of the solid in ether is dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title product as a yellow foam which is identified by NMR spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:27][C@H:28]4[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]4)[C:15]([C:17]([C:20]4[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=4)(O)[CH3:18])=[N:16][C:12]=3[CH:11]=[C:10]([C:35]#[N:36])[N:9]=2)[CH:5]=[N:6][CH:7]=1.CCN(S(F)(F)[F:43])CC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:27][C@H:28]4[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]4)[C:15]([C:17]([F:43])([C:20]4[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=4)[CH3:18])=[N:16][C:12]=3[CH:11]=[C:10]([C:35]#[N:36])[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(O)(c1ncccc1F)c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Solvent: ClCCl
Product: CC(F)(c1ncccc1F)c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Reaction time: 1 h

Procedure:
To a solution of 4-(5-chloropyridin-3-yl)-2-[(1RS)-1-(3-fluoropyridin-2-yl)-1-hydroxyethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (156 mg, 0.31 mmol) in CH2Cl2 (10.0 mL) at −40° C. under a nitrogen atmosphere was added DAST (0.08 mL, 0.22 mmol), and the resulting solution was stirred at this temperature for 1 hour. The reaction mixture was then quenched with a saturated aqueous solution of NaHCO3 (5 mL) and extracted with CH2Cl2 (2×15 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. Purification of the resulting residue on a silica gel column (0 to 100% ethyl acetate/hexanes) afforded 4-(5-chloropyridin-3-yl)-2-[(1RS)-1-fluoro-1-(3-fluoropyridin-2-yl)ethyl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS APCI calcd. for C27H25ClF2N6 [M+H]+ 507. found 507. The two enantiomers were separated on a chiralpak-AD column (15% IPA/heptane) to afford faster eluting Enantiomer A and slower eluting Enantiomer B.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])=[N:15][CH:14]=3)[CH:10](C=C=O)[CH2:9][CH2:8][CH:7]([N:33]3[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]3)[C:6]=2[CH:46]=1.Cl.[OH2:48].[OH-].[Na+].[O:51]1[CH2:56][CH2:55]OCC1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])=[N:15][CH:14]=3)[CH:10]([CH2:55][C:56]([OH:51])=[O:48])[CH2:9][CH2:8][CH:7]([N:33]3[CH2:34][CH2:35][NH:36][CH2:37][CH2:38]3)[C:6]=2[CH:46]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCC(C=C=O)N(C(=O)c3ccc(NC(=O)c4ccccc4Cl)nc3)c3ccc(Cl)cc32)CC1
Reactant: C1COCCO1
Reactant: O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CC1CCC(N2CCNCC2)c2cc(Cl)ccc2N1C(=O)c1ccc(NC(=O)c2ccccc2Cl)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-chloro-5-(4-t-butoxycarbonyl-1-piperazinyl)-carbonylmethyl-1-[6-(2-chlorobenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.2 g)in dioxane (20 ml)is added 5 N hydrochloric acid (2 ml), and the mixture is stirred at room temperature overnight. Water is added to the reaction mixture, and the mixture is made basic with aqueous sodium hydroxide solution, and extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography, and recrystallized from ethyl acetate-diethyl ether to give 7-chloro-5-(1-piperazinyl)carboxymethyl-1-[6-(2-chlorobenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.54 g) as white powder.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]#N)[CH:8]=1)(=O)C.[OH-:15].[K+].[CH3:17][OH:18]>>[OH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]([O:18][CH3:17])=[O:15])[CH:8]=1
Reactant: CC(=O)OCCc1ccnc(C#N)c1
Reactant: CO
Reactant: [OH-]
Agent: [K+]
Product: COC(=O)c1cc(CCO)ccn1
Temperature: 25 °C

Procedure:
A 1 l. round bottom flask was charged with 18.24 g (0.096 mol) of 4-[2-(acetyloxy)ethyl]-2-pyridinecarbonitrile and 380 ml of methanol. To the reaction mixture was added 96 ml of 5N aqueous potassium hydroxide and the reaction mixture was refluxed overnight with stirring. The reaction mixture was cooled and concentrated under vacuum. To the residue was added methanol saturated with hydrochloric acid (400 ml), and the resulting mixture was heated to reflux for 30 minutes, cooled and concentrated under vacuum. To the residue was added 400 ml of methanol saturated with hydrochloric acid. The mixture was refluxed overnight, cooled to room temperature and concentrated under vacuum. The mixture was partitioned between methylene chloride and 20% by weight potassium bicarbonate in water. The organic layer was separated, and the aqueous layer was extracted three times with methylene chloride and one time with diethyl ether. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide 11.51 g of the desired compound. The aqueous layer was concentrated to approximately half its original volume, extracted three times with methylene chloride and one time with diethyl ether. The organic extracts were combined, dried over anhydrous sodium sulfate and concentrated under vacuum as described above to provide an additional 1.15 g of the desired compound. The crude products were combined and purified by high pressure liquid chromatography to provide 9.02 g of methyl 4-(2-hydroxyethyl)-2-pyridinecarboxylate as a clear oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([Br:19])[CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=1.[CH2:20]([O:22][C:23](=[O:34])[CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([SH:32])=[CH:28][C:27]=1[CH3:33])[CH3:21]>>[CH2:20]([O:22][C:23](=[O:34])[CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:2]2[CH:3]=[C:4]([O:5][C:6]3[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=3)[CH:16]=[C:17]([Br:19])[CH:18]=2)=[CH:28][C:27]=1[CH3:33])[CH3:21]
Reactant: CCOC(=O)COc1ccc(S)cc1C
Reactant: FC(F)(F)c1ccc(Oc2cc(Br)cc(Br)c2)nc1
Product: CCOC(=O)COc1ccc(Sc2cc(Br)cc(Oc3ccc(C(F)(F)F)cn3)c2)cc1C

Procedure:
2-(3,5-Dibromo-phenoxy)-5-trifluoromethyl-pyridine (2.5 g; 6.3 mmol) and (4-Mercapto-2-methyl-phenoxy)-acetic acid ethyl ester (1.1 g; 4.9 mmol) was condensed to give the title product applying the procedure described for {4-[3-Bromo-5-cyclopentylmethoxyphenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester. The crude product was purified by flash chromatography (heptane→ethyl acetate:heptane 2:9). Yield 1.4 g (53%). HPLC-MS: m/z: 544.3 (M+2); Rt: 2.80 min.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:14]2[N:10]([C:11]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:12]3[C:18](=[O:19])[N:17]([CH3:20])[C:16](=[O:21])[N:15]([CH3:22])[C:13]3=2)[CH2:9][CH:8]=1)(=O)=O.[Br-].[Li+].C([Sn](CCCC)(CCCC)[C:38]1[O:39][C:40]([CH3:43])=[CH:41][CH:42]=1)CCC>C1COCC1.CCOCC>[CH3:22][N:15]1[C:13]2=[C:14]3[N:10]([C:11]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[C:12]2[C:18](=[O:19])[N:17]([CH3:20])[C:16]1=[O:21])[CH2:9][CH:8]=[C:7]3[C:38]1[O:39][C:40]([CH3:43])=[CH:41][CH:42]=1
Reactant: Cn1c(=O)c2c(-c3ccccc3)n3c(c2n(C)c1=O)C(OS(=O)(=O)C(F)(F)F)=CC3
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C)o1
Agent: [Br-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(C2=CCn3c(-c4ccccc4)c4c(=O)n(C)c(=O)n(C)c4c32)o1

Procedure:
1,3-Dimethyl-2,4-dioxo-5-phenyl-2,3,4,7-tetrahydro-1H-pyrimido[4,5-a]pyrrolizin-9-yl trifluoromethanesulfonate (step 4) (100 mg, 0.227 mmol), Cul (4.31 mg, 0.023 mmol), lithium bromide (39.4 mg, 0.453 mmol), tributyl(5-methylfuran-2-yl)stannane (168 mg, 0.453 mmol) in THF (2 ml) and Pd-118 (14.77 mg, 0.023 mmol) were heated to reflux for 10 mins. The reaction mixture was filtered through a glass filter paper and the filtrate concentrated in vacuo. The crude product was dissolved in the minimum amount DCM/EtOAc and loaded onto a 12 g silica cartridge and eluted with 0-80% EtOAc in iso-hexane. The desired product was eluted at 30% EtOAc. The relevant fractions were combined and concentrated to yield a yellow solid. The isolated solid was suspended in Et2O and the solid filtered to yield the title product.