Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1C=CC=CC=1.[N:16]#[C:17][NH2:18].[C:19](O)(C(F)(F)F)=O.BrC#N>>[CH2:9]([O:8][CH:1]1[CH2:2][N:16]([C:17]#[N:18])[CH2:19]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)C(F)(F)F
Reactant: N#CN
Reactant: c1ccc(COCc2ccccc2)cc1
Agent: N#CBr
Product: N#CN1CC(OCc2ccccc2)C1

Procedure:
Following general procedure 12, to a cold (0° C.), stirred solution of the alcohol (46) (173 mg, 1 equiv.) in DMF (2 mL) was added NaH,(60% in oil, 60 mg, 1.5 equiv.). The suspension was stirred at 0° C. for 30 minutes followed by the addition of the benzyl chloride (230 uL, 2 equiv.). The resulting suspension was poured into H2O and extracted with Et2O (3×). The combined organic extracts were washed with H2O and brine, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution: 10% EtOAc in hexane to 25% EtOAc in hexane) to afford the desired benzyl ether. The N-Boc group of the benzyl ether was then converted to the cyanamide (N—CN) following general procedure 3 (i.e. successive treatment with TFA and BrCN). The crude material was purified by flash chromatography (gradient elution: 10% EtOAc in hexane to 33% EtOAc in hexane) to afford the desired product 3-(benzyloxy)-1-cyanoazetidine (59).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[CH2:4][OH:5].Cl[C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[N:11]=[C:10]([NH:20][S:21](=[O:33])(=[O:32])[NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=2)[C:9]=1[O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[O:41][CH3:42]>C(COC)OC>[OH:5][CH2:4][CH2:3][O:6][C:8]1[N:13]=[C:12]([C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)[N:11]=[C:10]([NH:20][S:21](=[O:32])(=[O:33])[NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=2)[C:9]=1[O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[O:41][CH3:42]
Reactant: OCCO
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1NS(=O)(=O)Nc1ccc(C(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccccc1Oc1c(NS(=O)(=O)Nc2ccc(C(C)C)cc2)nc(-c2ccncc2)nc1OCCO
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (17 mg, 60% dispersion in mineral oil) was added to ethylene glycol (1.2 ml) followed by addition of dimethoxyethane (0.5 ml). Stirring was continued for 30 min, then 4-i-propyl-phenyl sulfamic acid-[6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidin-4-yl]-amide (45 mg, Referential Example 1e)) was added and the reaction mixture was heated to 80° C. for 48 h. The solvents were evaporated, water (10 ml) and a 10% solution of citric acid was added until the pH was 3 followed by extraction with EtOAc. The organic layers were dried over sodium sulfate and the solvent was evaporated. The crude product was purified by chromatography through silicagel with EtOAc to give 4-i-propyl-phenyl sulfamic acid-[6-(2-hydroxy-ethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidin-4-yl]-amide (38 mg). tR=4.56 min, (LC); [M+H]+=552.36 (ES+).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[C:19]2[NH:20][C:21]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)([C:24]([NH2:26])=[O:25])[CH2:22][O:23][C:18]=2[CH:17]=[CH:16][CH:15]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[O:4]=[C:2]1[N:20]2[C:21]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)([C:24]([NH2:26])=[O:25])[CH2:22][O:23][C:18]3=[C:19]2[C:14](=[CH:15][CH:16]=[CH:17]3)[NH:13]1
Reactant: NC(=O)C1(c2ccccn2)COc2cccc(N)c2N1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: NC(=O)C1(c2ccccn2)COc2cccc3[nH]c(=O)n1c23
Reaction time: 1 h
Yield: 192.9 %

Procedure:
Triphosgene (20 mg, 0.07 mmol) was added to a solution of 5-amino-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carboxamide (40 mg, 0.2 mmol) in tetrahydrofuran (5 mL) and N,N-diisopropylethylamine (60 μL, 0.3 mmol) at room temperature. The reaction was stirred for 1 h and then partitioned between ethyl acetate and water. The combined organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude 2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-4-carboxamide (0.040 g. 80%). LCMS calculated for C15H13N4O3 (M+H)+: m/z=297.1. found: 297.1.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C@H:12]([CH2:30][O:31][C:32](=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:13][CH2:14][O:15][C:16](=[O:29])[C@H:17]([CH:26]([CH3:28])[CH3:27])[NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[C:4](Cl)[N:3]=1.C([O-])=O.[NH4+]>CO.C(OCC)(=O)C.[Pd]>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C@H:12]([CH2:30][O:31][C:32](=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:13][CH2:14][O:15][C:16](=[O:29])[C@H:17]([CH:26]([CH3:28])[CH3:27])[NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:4][N:3]=1
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC[C@H](CCOC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)Cn1cnc2c(Cl)nc(N)nc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCC(=O)OC[C@H](CCOC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)Cn1cnc2cnc(N)nc21
Reaction time: 1 h

Procedure:
To the solution of (R)-2-amino-9-(2-stearoyloxymethyl-4-(N-tert-butoxycarbonyl-L-valyloxy)butyl)-6-chloropurine (240 mg, 0.33 mmole) in methanol/ethyl acetate (6 ml, 3:1 V/V) were added ammonium formate (105 mg, 1.65 mmole) and 10% palladium on carbon (15 mg). The reaction was kept under reflux for 1 hour and recharged with ammonium formate (70 mg). After one hour more the TLC showed completion of the reaction and the mixture was filtered through Celite and washed extensively with ethanol. The filtrate was evaporated and purified by silica gel column. Yield: 193 mg.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][OH:21])[CH:18]=3)[CH:13]=[CH:12]2)=[CH:7][CH:6]=1)[CH3:2].[C:23](OC(=O)C)(=[O:25])[CH3:24].N1C=CC=CC=1.O>ClCCl>[CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][O:21][C:23](=[O:25])[CH3:24])[CH:18]=3)[CH:13]=[CH:12]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2ccc3ccc(CO)cc32)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(-n2ccc3ccc(COC(C)=O)cc32)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 66.1 %

Procedure:
To a solution of 4-(6-formylindol-1-yl)benzoic acid ethyl ester in a mixed solvent of tetrahydrofuran (3 mL) and methanol (10 mL) was added sodium borohydride (0.075 g) at 0° C., and this mixture was stirred at room temperature for 0.5 hours. This reaction mixture was poured into a saturated aqueous ammonium chloride solution and this mixture was extracted with ethyl acetate. This organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 4-(6-hydroxymethyl-indol-1-yl)benzoic acid ethyl ester (0.38 g). To a solution of 4-(6-hydroxymethyl-indol-1-yl)benzoic acid ethyl ester (0.09 g) in dichloromethane (1 mL) were added acetic anhydride (0.093 g) and pyridine (0.024 g), and this mixture was stirred at room temperature for 2 days. This mixture was poured into water and the resulting mixture was extracted with ethyl acetate. This organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (0.068 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][C:11](NCC(OC)=O)=[N:10]2)=[CH:5][CH:4]=1.[CH3:20][O:21][C:22](=[O:43])[CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:44](Cl)Cl>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:13]=[CH:12][C:11](/[CH:44]=[CH:23]/[C:22]([O:21][CH3:20])=[O:43])=[N:10]2)=[CH:7][CH:8]=1
Reactant: COC(=O)CNc1ccn(-c2ccc(OC)cc2)n1
Reactant: ClCCl
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: COC(=O)/C=C/c1ccn(-c2ccc(OC)cc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
To a solution of 1-[(4-methoxy)phenyl]-3-(carboxaldehyde)-1H-pyrazole-5-[(2′-tert-butylaminosulfonyl-[1,1′]-biphen-4-yl)carboxyamide (1.30 g, 2.44 mmol) in 30 mL of methylene chloride was added methyl(triphenylphosphoranylidene)acetate (0.98 g, 2.92 mmol). The mixture was allowed to stir at ambient temperature for 18 h. The volatiles were removed in vacuo and the residue was purified by flash chromatography (elution with 1:1 ethyl acetate/hexane) to afford 1.2 g (83%) of the title compound. LRMS (ES+): 589.1 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:10]=[N:11][C:12]([Cl:32])=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[C:22](=O)[C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[F:30])(C)(C)C.FC(F)(F)C(O)=O.O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[Cl:32][C:12]1[N:11]=[CH:10][C:9]2[CH2:8][N:7]=[C:22]([C:23]3[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=3[F:30])[C:16]3[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=3[C:14]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)NCc1cnc(Cl)cc1-c1ccc(Cl)cc1C(=O)c1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Fc1cccc(F)c1C1=NCc2cnc(Cl)cc2-c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
Tert-butyl({6-chloro-4-[4-chloro-2-(2,6-difluorobenzoyl)phenyl]pyridin-3-yl}-methyl)carbamate (165.0 mg, 0.3345 mmol) was dissolved in methylene chloride (5 mL). Trifluoroacetic acid (5 mL, 0.06 mol) was added and the reaction was stirred at room temperature under an atmosphere of nitrogen overnight. Water (20 mL) and methylene chloride (15 mL) were added and the resulting mixture was stirred while solid sodium carbonate (4.50 g, 0.04 mol) was slowly added with stirring. The resulting basic mixture was stirred at room temperature for 30 minutes and then transferred to a separatory funnel. The organic layer was separated and the aqueous phase was extracted with additional methylene chloride (10 mL). The organic extracts were combined, washed with water (10 mL) and brine (10 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting white solid was purified by column chromatography on silica gel (elution gradient from dichloromethane to 7.5% ethyl acetate/dichloromethane) to yield 2,9-dichloro-7-(2,6-difluorophenyl)-5H-pyrido[3,4-d][2]-benzazepine (108 mg, 86%) as a white solid. The product structure was confirmed by NMR and MS.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH2:14])[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26]1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][C:34]([C:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[NH:25][CH:26]=2)=[O:35])[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1)c1c[nH]c2ccccc12

Procedure:
200 mg (0.550 mmol) of (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine are reacted in analogy to Example 4a with 106 mg (0.661 mmol) of indole-3-carboxylic acid, 168 mg (0.661 mmol) of bis(2-oxo-3-oxazolidinyl)phosphinic chloride and 169 μl (1.21 mmol) of triethylamine. The title compound ##STR86## is obtained (92 mg, 33%) as oil. TLC:methylene chloride/methanol/cone. ammonia (350:50:1) Rf =0.61, FD-MS:M+ =505, 507; IR:3450, 3260, 1770, 1635 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13]C)[CH:9]=2)[CH:4]=1.[Na].Cl.O>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8](=[O:13])[CH2:7][CH2:6]2
Reactant: COc1ccc2cc(OC)ccc2c1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)CCC(=O)C2
Temperature: 25 °C
Yield: 125.5 %

Procedure:
A suspension of 2,6-dimethoxynaphthalene (20.0 g, Aldrich) in 200 mL of anhydrous EtOH was heated to reflux under a stream of nitrogen. Sodium spheres (18 g, Aldrich) were added gradually to the hot suspension over a period of 2 hours. Additional ETOH (50 ml) was added and the reaction was heated until all of the sodium had dissolved. The solution was cooled to room temperature and placed in an ice bath. The addition of 6 N HCl brought the solution to pH 6, and additional HCl (10 mL) was added. The solution was heated to reflux for 0.5 h. The golden mixture was cooled to room temperature, H2O (200 mL) was added, and the solution was extracted with ET2O. The combined ET2O extracts were dried (Na2SO4), filtered, and concentrated to afford 6-methoxy-2-tetra-lone as a red oil (23.5 g). Triethyl phosphono-acetate (29 mL, Aldrich) was added dropwise to a suspension of hexane-washed sodium hydride (5.8 g of 60% dispersion) in benzene (80 mL) cooled in an ice bath. The phos-phonate solution was stirred at room temperature for 0.5 h, and the ice bath was replaced. A solution of 6-methoxy-2-tetralone (23.5 g) in benzene (20 mL) was added to the phosphonate solution over 10 minutes, and the reaction was allowed to stir at room temperature overnight. The reaction was poured into H2O and extracted with EtOAc (3×150 mL). The combined extracts were dried (Na2SO4), filtered, and concentrated to afford a brown oil which was purified using silica gel chromatography. Elution with 10% EtOAc/hexane afforded the title compound (27 g) as a yellow oil. NMR (300 MHz, CDCl3) δ6.98 (d, J=9.03 Hz, 1 H), 6.79-6.70 (m, 2H), 6.35 (s, 1H), 3.94 (q, J=7.11 Hz, 2H), 3.58 (s, 3H), 2.99 (s, 2H), 2.61 (t, J 8.11 Hz, 2H), 2.14 (t, J=8.07 Hz, 2H), 1.08 (t, J 7.14 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12](/[C:15](/[CH3:19])=[CH:16]/[CH2:17][OH:18])=[CH:11][CH:10]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH2:20]([O:22][C@@H:23]([CH2:29][C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:21]>>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12](/[C:15](/[CH3:19])=[CH:16]/[CH2:17][O:18][C:33]3[CH:32]=[CH:31][C:30]([CH2:29][C@H:23]([O:22][CH2:20][CH3:21])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:35][CH:34]=3)=[CH:13][CH:14]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: C/C(=C\CO)c1ccc(-c2cc(Br)cc(Br)c2)cc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cc(Br)cc(Br)c3)cc2)cc1)OCC
Yield: 84 %

Procedure:
The title compound (177 mg, 83%) was prepared as a colourless gum from (E)-3-(3′,5′-dibromo-biphenyl-4-yl)-but-2-en-1-ol (135 mg, 0.35 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (90 mg, 0.38 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13](C(O)=O)[C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1(C)C=CC=CC=1.CS(C)=O.CC(OC)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(C(=O)O)C(=O)O)C1
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N1CC[C@H](CC(=O)O)C1
Yield: 92 %

Procedure:
A suspension of (R)-2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)malonic acid (15 g, 55 mmol) in toluene (150 mL) and dimethylsulfoxide (2 mL) was heated to reflux for a period of 2 h. The mixture was allowed to reach ambient and diluted with MTBE (150 mL). The organic solution was washed with 10% aqueous citric acid (2×200 mL), and the solvent was removed under vacuum to afford 11.6 g of (R)-2-(1-(tert-butoxycarbonyl)-pyrrolidin-3-yl)acetic acid as an off-white solid (92% yield). 1H NMR (DMSO-d6, 400 MHz): δ 12.1 (s, 1H); 3.36-3.48 (m, 1H); 3.20-3.34 (m, 1H); 3.05-3.19 (m, 1H; 2.72-2.84 (m, 1H); 2.30-2.42 (m, 1H), 2.22-2.30 (m, 2H); 1.85-2.00 (m, 1H); 1.38-1.54 (m, 1H), 1.35 (2, 9H).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12]OS(C2C=CC(C)=CC=2)(=O)=O)=[C:8]([S:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F-:36].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][F:36])=[C:8]([S:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCc2c(SCc3ccc(C(C)(C)C)cc3)cnn(C(C)(C)C)c2=O)cc1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1ccc(CSc2cnn(C(C)(C)C)c(=O)c2CF)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a 15 ml round bottom flask charged with 2-tert-butyl-4-p-toluenesulfonyloxymethyl-5-(4-tert-butylbenzyl)thio-3(2H)-pyridazinone (0.5 g, 0.972 mmol) is added 4.86 ml of tetra-butylammonium fluoride solution (1M in THF, 4.86 mmol). The mixture is first stirred at room temperature for 15 minutes after which it is heated for 15 minutes at 100° C. The solution is then cooled to room temperature and to it is added dichloromethane followed by water. The layers were separated and the organic layer is washed with water and then dried. The organic layer is then concentrated and subjected to purification using silica gel flash chromatography (ethyl acetate/hexanes) to obtain the above compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:5]=[CH:6][C:7]=1[NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]1.[C:20](N1C=CN=C1)(N1C=CN=C1)=[S:21].O>CN(C)C=O>[OH:15][C@H:12]1[CH2:13][CH2:14][C@H:9]([N:8]2[C:7]3[CH:6]=[CH:5][C:4]([C:16]([F:17])([F:18])[F:19])=[CH:3][C:2]=3[NH:1][C:20]2=[S:21])[CH2:10][CH2:11]1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(C(F)(F)F)ccc1N[C@H]1CC[C@H](O)CC1
Solvent: O
Solvent: CN(C)C=O
Product: O[C@H]1CC[C@H](n2c(=S)[nH]c3cc(C(F)(F)F)ccc32)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 3-amino-4-(trans-4-hydroxycyclohexylamino)benzotrifluoride (300 mg) in N,N-dimethylformamide (3 mL) was added 1,1′-thiocarbonyldiimidazole (234 mg), and the mixture was stirred at room temperature under nitrogen atmosphere for 15 hours. Water was added to the mixture, and the resulting precipitate was collected by filtration. The obtained solid was washed successively with water and diethyl ether to give 1-(trans-4-hydroxycyclohexyl)-5-trifluoromethyl-2,3-dihydro-1H-benzimidazol-2-thione (242.8 mg) as a pale brown solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[N:12]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[N:11]=[CH:10][CH:9]=2)=[CH:6][N:5]2[C:21](=[O:24])[NH:22][N:23]=[C:4]2[C:3]=1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1.Br[CH2:36][CH2:37][CH2:38][S:39]([CH3:42])(=[O:41])=[O:40]>>[CH3:42][S:39]([CH2:38][CH2:37][CH2:36][N:22]1[C:21](=[O:24])[N:5]2[CH:6]=[C:7]([C:8]3[N:12]([C:13]4[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=4)[N:11]=[CH:10][CH:9]=3)[C:2]([CH3:1])=[C:3]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=3)[C:4]2=[N:23]1)(=[O:41])=[O:40]
Reactant: CS(=O)(=O)CCCBr
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2c(=O)[nH]nc2c1-c1cccc(C(F)(F)F)c1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2c(=O)n(CCCS(C)(=O)=O)nc2c1-c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 4-{5-[7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Ex. 9, 70 mg. 0.152 mmol) and 1-bromo-3-methanesulfonyl-propane (53 mg, 0.264 mmol) using a similar method to that employed for Example 11 (27 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][C:11](=[O:13])[NH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[NH2:29][C@@H:30]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C@H:31]([OH:42])[CH2:32][N:33]1[CH2:37][CH2:36][CH2:35][C@H:34]1[C:38]([F:41])([F:40])[F:39].CN1CCOCC1>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([NH:29][C@@H:30]([CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[C@H:31]([OH:42])[CH2:32][N:33]1[CH2:37][CH2:36][CH2:35][C@H:34]1[C:38]([F:41])([F:39])[F:40])=[O:16])[CH2:10][C:11](=[O:13])[NH2:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: N[C@@H](Cc1ccccc1)[C@H](O)CN1CCC[C@H]1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN1CCC[C@H]1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirred solution of 731 mg (3.12 mmol) of N-(tert-butoxycarbonyl)-L-asparagine in 6 ml of anhydrous DMF was treated at 0° C. with 530 mg (3.44 mmol) of HOBT and 1.39 g (3.28 mmol) of CMTC. A solution of 1,114 mg (2.84 mmol) of the compound from Example 3 and 1.6 ml (14.20 retool) of N-methylmorpholine in 8 ml of DMF was then added. The cooling bath was removed and the mixture was stirred at room temperature for 3 h. It was then concentrated in vacuo and the residue was partitioned between 40 ml of ethyl acetate and 40 ml of water. The water phase was extracted with 10 ml of ethyl acetate, and the combined extracts were washed with 50 ml of water and dried over MgSO4. After evaporation of the solvent in vacuo and chromatography of the crude product on 200 g of silica gel (dichloromethane:methanol 9:1), 1.42 g (89% of theory) of the title compound were obtained as crystals. Melting points: 104° C. Rf =0.15, I(9:1) MS(FAB): m/e=517 (M+H)+
Reaction SMILES: FC(F)(F)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][C:14]3[C:19]([N:20]=2)=[CH:18][CH:17]=[C:16]([C:21]2([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:23][CH2:22]2)[N:15]=3)=[C:8]([F:30])[CH:7]=1)=O.CI.[CH:35]([N-]C(C)C)(C)C.[Li+]>C1COCC1.C(Cl)Cl>[F:30][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=1[C:12]1[S:13][C:14]2[C:19]([N:20]=1)=[CH:18][CH:17]=[C:16]([C:21]1([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:23][CH2:22]1)[N:15]=2)[N:5]([CH3:3])[CH3:35]
Reactant: O=C(Nc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1)C(F)(F)F
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2,2,2-Trifluoro-N-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)acetamide (80 mg, 0.175 mmol) was dissolved in THF (1.7 mL) before methyl iodide (13 μl, 0.210 mmol) and lithium diisopropylamide (175 μl, 0.350 mmol) were added and stirred at 0° C. for 30 min. The reaction mixture was diluted with 75 mL of DCM, added to a separatory funnel, partitioned with sodium bicarbonate (saturated, aqueous), washed 2 times with 50 mL of water, separated, dried over sodium sulfate, and concentrated via rotovap to give the title compound after flash chromatography. MS (ESI) m/z: Calculated: 389.1; Observed: 390.1 (M++1).