Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([O-])(C)C.[K+].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1.F[C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]>CS(C)=O.C(OCC)(=O)C>[F:31][C:29]1[CH:30]=[CH:23][C:24]([C:25]#[N:26])=[C:27]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[O:15])=[CH:12][CH:13]=2)[CH:28]=1
Reactant: Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: N#Cc1ccc(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(F)cc1Nc1ccc(C(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 108.6 %

Procedure:
KOtBu (0.968 g, 8.63 mmol) was dissolved into DMSO (3 ml) in a 100 ml round bottom flask. (4-aminophenyl)(morpholino)methanone (1.631 g, 7.91 mmol) in 7 ml of DMSO was added. The mixture was stirred for 15 mins at r.t. 2,4-difluorobenzonitrile (1 g, 7.19 mmol) in 3 ml DMSO was added slowly into the mixture for about 5 mins. The resulting mixture was stirred for 1.5 hrs at r.t. The mixture was diluted with ethyl acetate and extracted with aqueous NH4Cl solution. The organic layer was then washed with water (4×), brine, dried with MgSO4 and concentrated. 2.54 g crude 4-fluoro-2-(4-(morpholine-4-carbonyl)phenylamino)benzonitrile (80% by LC/MS) was obtained. MS (ESI) m/z 326.11 (M+H)+.
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[OH-].[Na+].Cl[CH2:11][C:12]([C:14]1[CH:23]=[CH:22][C:17]2[O:18][CH2:19][CH2:20][O:21][C:16]=2[CH:15]=1)=[O:13]>CCO.O>[O:18]1[C:17]2[CH:22]=[CH:23][C:14]([C:12](=[O:13])[CH2:11][S:3][C:2]3[S:1][CH2:7][C:5](=[O:6])[N:4]=3)=[CH:15][C:16]=2[O:21][CH2:20][CH2:19]1
Reactant: O=C1CSC(=S)N1
Reactant: O=C(CCl)c1ccc2c(c1)OCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C1CSC(SCC(=O)c2ccc3c(c2)OCCO3)=N1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Rhodanine (0.052 g, 0.388 mmol, 1.0 eq.) was dissolved in EtOH (2 ml) and 2 M NaOH (0.275 ml, 0.550 mmol, 1.42 eq.) with vigorous stirring. Once the Rhodanine was completely dissolved, 6-Chloroacetyl-1,4-benzodioxane (0.080 g, 0.380 mmol, 0.98 eq.) was added with constant stirring. (It should be noted that α-chloro ketones were used when the corresponding α-bromo ketones were not available.) The reaction was mixed overnight at 40° C. After 18 hrs the reaction was removed from the heat and left stirring at room temp for 48 hrs. The resulting reaction mixture was then diluted with water (5 ml) and extracted with dichloromethane (3×5 ml). The organic layer was dried over Na2SO4 and then evaporated to yield an oil. The oil was purified by chromatotron using a 50/50 mixture of ethyl acetate in hexanes as the mobile phase. The purified product, Compound 34, was then recrystallized in hexanes to complete its purification (20 mg, 0.0646 mmol, 17%). The product was characterized by 1H-NMR: (CDCl3) 7.55 (q, 2H), 6.93 (d, 1H), 4.93 (s, 2H), 4.31 (m, 4H), 4.02 (s, 2H) ppm. In addition LCMS [ES+] analysis yielded a single peak, 310 [M]+ m/e.
Reaction SMILES: C[O-].[Na+].[C:4]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[O:12])=[CH:9][CH:8]=1)(=[O:6])[CH3:5].[CH3:16][O:17][C:18]1[O:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1.CO>CN(C)C=O>[CH3:16][O:17][C:18]1[O:22][C:21](/[CH:23]=[CH:5]/[C:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[O:12])=[CH:9][CH:8]=2)=[O:6])=[CH:20][CH:19]=1
Reactant: COc1ccc(C=O)o1
Reactant: CC(=O)c1ccc(C(N)=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(/C=C/C(=O)c2ccc(C(N)=O)cc2)o1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
Sodium methoxide (in portions) was added, over a time interval of about three minutes, to 4-acetyl-benzamide (1.38 g, 8.5 mmol) and 5-methoxy-furan-2-carbaldehyde (1.31 g, 10.6 mmol) in a 1:1 mixture of methanol and dimethylformamide (16 mL). The resulting solution was placed under N2 and stirred overnight at 45° C. The reaction mixture was then evaporated to dryness under vacuum, followed by the addition of water and brine (100 mL) to the resulting residue. The aqueous solution was extracted with ethyl acetate (125 mL×3) and the combined organic layers were washed with brine (100 mL) and dried over MgSO4. The crude reaction mixture of 4-[(E)-3-(5-methoxy-furan-2-yl)-acryloyl]-benzamide and unreacted 4-acetyl acetamide is used without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl[CH2:11][C:12]([O-:14])=[O:13].[Na+]>O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][CH2:11][C:12]([OH:14])=[O:13])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(N)cc1
Reactant: O=C([O-])CCl
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(NCC(=O)O)cc1
Temperature: 0 °C
Yield: 72.7 %

Procedure:
77.4 g (0.66 mol) of 4-aminobenzonitrile and 150 g (1.31 mol) of sodium chloroacetate were suspended in 1.1 L of water, and the resulting mixture was stirred at reflux temperature for 6.5 hours. After cooling to 0° C., the resulting suspension was stirred at this temperature overnight. The solid was filtered and washed with 200 mL of water. The resulting solid was suspended in 200 mL of ethyl acetate and stirred at room temperature for 1 hour. The solid was filtered, washed with 400 mL of ethyl acetate and dried at 60° C. under vacuum for 5 hours to yield 84.5 g of 2-(4-cyanophenylamino)acetic acid as an off-white solid. Yield: 73.2%. Purity (HPLC, method 3): 98.4%.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[CH:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[N:30]=[CH:29][C:28]([F:31])=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>CC#N>[F:31][C:28]1[CH:27]=[N:26][C:25]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)=[O:11])=[N:30][CH:29]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: Cc1ccc(-n2cccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2cccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(F)cn2)c1
Temperature: 100 °C

Procedure:
A mixture of ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1H-pyrazol-1-yl)phenyl)methanone (30 mg, 96 μmol), 2-chloro-5-fluoropyrimidine (18 μl, 144 μmol) and anhydrous DIPEA (50 g, 288 μmol) in CH3CN (2 mL) was heated at 100° C. for 3 days. The mixture was cooled to rt and the solvent was removed in vacuo. The crude was dissolved in EtOAc and washed with satd. aq. NaHCO3, brine, and dried (MgSO4). The solvent was removed and the crude was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 409 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:27]=1[C:28](Cl)=[O:29].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:29])[C:27]4[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:26]=4[Cl:25])=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1cc(Cl)ccc1Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.4 %

Procedure:
A mixture of 0.625 g (2 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.629 g (3 mmol) of 2,5-dichlorobenzoyl chloride, 0.303 g (3 mmol) of triethylamine and 15 mg of 4-(dimethylamino)pyridine in 10 ml of dichloromethane is stirred at room temperature for 3 hours. The mixture is washed with water, 1N HCl, H2O, 1M NaHCO3, brine and dried (Na2SO4). The solvent is removed to give crystals. Recrystallization from hexane-CH2Cl2 gives 0.16 g of white crystals, m.p. 203°-231° C.
Reaction SMILES: [ClH:1].C(O[C:7]([N:9]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([F:23])=[C:18]([F:22])[C:19]=2[F:21])[C:14](=[O:24])[C:13]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:12]1)C)=O)(C)(C)C.C(OC(C)C)(C)C>C(OCC)(=O)C>[ClH:1].[F:23][C:17]1[CH:16]=[C:15]2[C:20](=[C:19]([F:21])[C:18]=1[F:22])[N:11]([NH:9][CH3:7])[CH:12]=[C:13]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:14]2=[O:24]
Reactant: CCOC(=O)c1cn(N(C)C(=O)OC(C)(C)C)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(NC)c2c(F)c(F)c(F)cc2c1=O
Reaction time: 2 h

Procedure:
To 4N hydrochloric acid solution (46 ml) in ethyl acetate was added ethyl 1-(N-tert-butoxycarbonyl-N-methylamino)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (9.20 g) under ice-cooling and the mixture was stirred at the same condition for 2 hours. Diisopropyl ether (90 ml) was added to the mixture to give a solid. The solid was collected by filtration, and dried over phosphorus pentaoxide under reduced pressure to give ethyl 6,7,8-trifluoro-1-methylamino-1,4-dihydro -4-oxoquinoline-3-carboxylate hydrochloride(6.26 g).
Reaction SMILES: C[N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:8][CH:9]=2)[C:4]([S:19]([CH:21]([CH3:23])[CH3:22])=O)=[C:3]1[C:24]([O:26][CH2:27][CH3:28])=[O:25].[I-].[Na+].F[C:32](F)(F)[C:33](OC(=O)C(F)(F)F)=[O:34]>O1CCCC1>[CH3:32][CH2:33][O:34][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:8][CH:9]=2)[C:4]([S:19][CH:21]([CH3:22])[CH3:23])=[C:3]1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)c1c(S(=O)C(C)C)c2cc(OCc3ccccc3)ccc2n1C
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(SC(C)C)c2cc(OCc3ccccc3)ccc2n1OCC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 81.8 %

Procedure:
A mixture of ethyl 1-methyl-3-[(1-methylethyl)sulfinyl]-5-(phenylmethoxy)-1H-indole-2-carboxylate (0.50 g, 1.3 mmol) and sodium iodide (0.69 g, 4.6 mmol) in 30 mL of tetrahydrofuran is cooled to 0° C. and treated dropwise with trifluoroacetic anhydride (1.0 mL, 1.5 g, 7.1 mmol). The mixture is stirred for 10 minutes, then quenched by pouring into 100 mL of cold 5% aqueous sodium bicarbonate solution. The mixture is extracted with ether, and the combined organic layers are washed with 5% aqueous sodium thiosulfate solution, followed by brine. The organic layer is dried (anhydrous magnesium sulfate) and evaporated to give 0.44 g (92%) of product; mp 94°-96° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)[N:4]=1.N1(C2C=C[C:25]([CH:26]=[O:27])=CC=2)C=CC=N1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:16]=[CH:15][C:12](/[CH:13]=[CH:25]/[CH:26]=[O:27])=[CH:11][CH:10]=2)[N:4]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: COc1ccnc(-c2ccc(C=O)cc2)n1
Product: COc1ccnc(-c2ccc(/C=C/C=O)cc2)n1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(4-methoxy-2-pyrimidinyl)benzaldehyde (prepared as described in Reference Example 13) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 241 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6]([CH3:26])=[C:7]([CH2:14][N:15]3[C:19](=[O:20])[C:18]4=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]4[C:16]3=[O:25])[C:8](=[O:13])[O:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:34][C:35](=[O:37])[CH3:36].CC(C)=O>C(Cl)Cl>[CH3:26][C:6]1[C:5]2[C:10](=[C:11]([CH3:12])[C:2]([O:1][CH2:34][C:35](=[O:37])[CH3:36])=[CH:3][CH:4]=2)[O:9][C:8](=[O:13])[C:7]=1[CH2:14][N:15]1[C:16](=[O:25])[C:17]2=[CH:24][CH:23]=[CH:22][CH:21]=[C:18]2[C:19]1=[O:20]
Reactant: CC(=O)CCl
Reactant: Cc1c(CN2C(=O)c3ccccc3C2=O)c(=O)oc2c(C)c(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(=O)COc1ccc2c(C)c(CN3C(=O)c4ccccc4C3=O)c(=O)oc2c1C
Temperature: 25 °C
Yield: 87.1 %

Procedure:
A slurry of 7-hydroxy-4,8-dimethyl-3-phthalimidomethylcoumarin (4.00 g, 11.5 mmol), potassium carbonate (4.5 g, 36.9 mmol), chloroacetone (1 mL, 11.5 mmol) and acetone (200 mL) were refluxed overnight. After the solution was allowed to cool to room temperature, CH2Cl2 (200 mL) was added and the resulting solid was filtered off. The remaining solution was cold decolorized with charcoal and the solvent evaporated. The resulting solid was stirred with water, vacuum filtered, and washed with water. After air drying, 4,8-dimethyl-7-(2-oxo)propyloxy-3-(phthalimidomethyl)coumarin (4.06 g, 87.1% ) was obtained as an off-white solid. 1H NMR (CDCl3): δ7.66-7.83 (m, 4H), 7.48 (d, J=8.8 Hz, 1H), 6.65 (d, J=8.8 Hz, 1H), 4.91 (s, 2H), 4.62 (s, 2H), 2.59 (s, 3H), 2.35 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][N:6]=1)(=[O:3])[CH3:2].[CH3:12][CH:13]([N:18]=[C:19]=[S:20])[C:14]([CH3:17])([CH3:16])[CH3:15]>N1C=CC=CC=1>[C:1]([NH:4][C:5]1[N:6]=[CH:7][C:8]([NH:11][C:19]([NH:18][CH:13]([CH3:12])[C:14]([CH3:17])([CH3:16])[CH3:15])=[S:20])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(N=C=S)C(C)(C)C
Reactant: CC(=O)Nc1ccc(N)cn1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(NC(=S)NC(C)C(C)(C)C)cn1
Temperature: 50 °C
Reaction time: 15 h
Yield: 79596.1 %

Procedure:
To a solution of 2-acetylamino-5-aminopyridine (150 mg, 0.99 mmol) in pyridine (1.5 ml), 213 mg (1.49 mmol) of 1,2,2-trimethylpropyl isothiocyanate was added dropwise, followed by stirring at room temperature for 22 hours, at 50° C. for 5 hours and further at room temperature for 15 hours. Then, the solvent was removed by distillation under reduced pressure. The residue was recrystallized from chloroform-hexane to obtain 232 g of the intended product as a flesh-colored powder (yield: 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27](O)=[O:28])[CH:5]=[CH:6][CH:7]=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH2:40][CH2:41][NH2:42])[CH:35]=[CH:36][C:37]=1[O:38][CH3:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH2:40][CH2:41][NH:42][C:27]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:12]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10]2)=[O:28])[CH:35]=[CH:36][C:37]=1[O:38][CH3:39]
Reactant: COc1ccc(CCN)cc1OC
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CCNC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3)C2c2cccc(Cl)c2)cc1OC
Yield: 45.1 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example 1d was reacted with 2-(3,4-dimethoxy-phenyl)ethyl amine (30.3 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) to at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid 2-(3,4-dimethoxy-phenyl)ethyl amide (53.6 mg, 45.07%).
Reaction SMILES: C(=O)([O-])O.[Na+].Cl.[NH2:7][OH:8].[C:9]([CH2:11][C@H:12]1[C@H:18]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[O:17][CH2:16][CH2:15][N:14]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:13]1)#[N:10].O>CS(C)=O>[NH2:10][C:9](=[N:7][OH:8])[CH2:11][C@H:12]1[C@H:18]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[O:17][CH2:16][CH2:15][N:14]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CC#N)C1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CC(N)=NO)C1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 108.1 %

Procedure:
Sodium hydrogen carbonate (872 mg, 10.38 mmol) was added to a suspension of hydroxylamine monohydrochloride (721 mg, 10.38 mmol) in DMSO (3 mL), and the mixture was stirred at 80° C. for 15 min. The precipitate was filtered off, and a solution of tert-butyl (6R,7R)-6-(cyanomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (500 mg, 1.30 mmol) in DMSO (4 mL) was added to the filtrate. The reaction mixture was stirred at 80° C. overnight. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (588 mg). This compound was used for the next reaction without purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].F[C:21]1[CH:26]=[CH:25][C:24]([S:27]([N:30]=[N+:31]=[N-:32])(=[O:29])=[O:28])=[CH:23][CH:22]=1.C(OC(=O)NCCC1C=CC(OS(C2C=CC(F)=CC=2)(=O)=O)=CC=1)(C)(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:21]2[CH:26]=[CH:25][C:24]([S:27]([N:30]=[N+:31]=[N-:32])(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Reactant: [N-]=[N+]=NS(=O)(=O)c1ccc(F)cc1
Agent: CC(C)(C)OC(=O)NCCc1ccc(OS(=O)(=O)c2ccc(F)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc(S(=O)(=O)N=[N+]=[N-])cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Dissolve [2-(4-hydroxyphenyl)ethyl]carbamic acid tert-butyl ester (0.594 g, 2.50 mmol) in DMF (12.5 mL). Add NaH (80% in mineral oil) (0.083 g, 2.75 mmol). Stir at room temperature for 30 minutes. Add 4-fluorobenzenesulfonyl azide (0.504 g, 2.50 mmol) and heat to 60° C. Remove DMF as an azeotrope with xylenes after 3.75 hours. Purify by flash 40 chromatography, eluting with 30% ethyl acetate in hexanes to give a mixture of (2-(4-(4-fluorobenzenesulfonyl)oxyphenyl)ethyl)carbamic acid tert-butyl ester and the title compound: HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 50-99% over 19 min], tR=16.1 min, 35% purity; TLC [silica gel 60 F254, 5% ethyl acetate in hexanes] Rf=0.49.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2([CH2:12][NH:13][C:14]3[N:19]=[N:18][C:17]([C:20]4[CH:21]=[C:22]5[C:26](=[CH:27][CH:28]=4)[NH:25][N:24]=[C:23]5[NH:29][CH2:30][CH2:31][NH:32]C(=O)OCC4C=CC=CC=4)=[CH:16][CH:15]=3)[CH2:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Si](I)(C)(C)C>C(#N)C.CO>[F:1][C:2]1[C:3]([C:8]2([CH2:12][NH:13][C:14]3[N:19]=[N:18][C:17]([C:20]4[CH:21]=[C:22]5[C:26](=[CH:27][CH:28]=4)[NH:25][N:24]=[C:23]5[NH:29][CH2:30][CH2:31][NH2:32])=[CH:16][CH:15]=3)[CH2:9][CH2:10][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCCNc1n[nH]c2ccc(-c3ccc(NCC4(c5ncccc5F)CCC4)nn3)cc12)OCc1ccccc1
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: CO
Product: NCCNc1n[nH]c2ccc(-c3ccc(NCC4(c5ncccc5F)CCC4)nn3)cc12
Reaction time: 0.25 h
Yield: 55.1 %

Procedure:
Benzyl 2-(5-(6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)-1H-indazol-3-ylamino)ethylcarbamate (48 mg, 84 μmol) was dissolved in acetonitrile (5 mL), and TMSI (0.5 mL) was added. The reaction was stirred for 15 min, diluted with methanol (15 mL), concentrated, and was directly purified by reverse phase column chromatography to yield 20 mg (88%) of N1-(5-(6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)-1H-indazol-3-yl)ethane-1,2-diamine as a yellow solid, m/z=433 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:15][CH2:14][N:13]([C:16]([C@H:18]([NH:28][C:29](=[O:41])[C:30]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])([CH3:32])[CH3:31])[CH2:19][O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:17])[CH2:12][CH2:11]3)[CH2:9][NH:8][C:5]2=[CH:6][CH:7]=1.CN1CCOCC1.[CH3:49][S:50](Cl)(=[O:52])=[O:51]>ClCCl>[CH3:49][S:50]([N:8]1[C:5]2[C:4](=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:10]2([CH2:11][CH2:12][N:13]([C:16]([C@H:18]([NH:28][C:29](=[O:41])[C:30]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])([CH3:32])[CH3:31])[CH2:19][O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:17])[CH2:14][CH2:15]2)[CH2:9]1)(=[O:52])=[O:51]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](COCc1ccccc1)C(=O)N1CCC2(CC1)CNc1ccc(F)cc12
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](COCc1ccccc1)C(=O)N1CCC2(CC1)CN(S(C)(=O)=O)c1ccc(F)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.134 g the intermediate from Step B in 5 mL of dichloromethane was added 0.080 mL of N-methylmorpholine, and 0.022 mL of methanesulfonylchloride and stirred at 0° C. for 30 min. The reaction mixture was diluted with an additional 5 mL of dichloromethane and washed with 5 mL of saturated sodium bicarbonate solution, brine (5 mL), dried over MgSO4 and concentrated. Flash chromatography of the residue over 20 g of silica gel gave 0.101 g of the desired product.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[CH:4]=[CH:3]1.[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:7][CH:5]1[CH2:6][C:2](=[O:1])[CH:3]=[CH:4]1
Reactant: C1=COCCC1
Reactant: O=C1C=CC(O)C1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1C=CC(OC2CCCCO2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
A solution of 4-hydroxy-2-cyclopentenone (1.41 g, 14.4 mmol) in tetrahydrofuran (24 mL) is treated with 3,4-dihydro-2H-pyran (2 mL) and pyridinium p-toluenesulfonate (500 mg, PPTS). The reaction is stirred at room temperature for 18 hours. The reaction mixture is then diluted with ethyl acetate (25 mL) and washed with 50% saturated brine (2×30 mL). The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The resulting crude brown oil is purified by filtration through a plug of silica gel (25 g, 33% ethyl acetate/hexane) to provide the title compound as a yellow oil (2.00 g, 76%); 1H NMR (CDCl3) δ 7.46 (2×dd, 1 H, J=16.3, 5.7 Hz), 6.2 (m, 1H), 4.9 (m, 1 H), 4.80 (d appt, 1 H, J=23.8, 2.9 Hz), 3.9 (m, 1 H), 3.6 (m, 1 H), 2.73 (2×dd, 1 H, J=18.4, 6.2 Hz), 2.35 (2×d, 1 H, J=18.4 Hz), 1.8 (m, 1 H), 1.6 (m, 4 H); IR (neat) νmax 2944, 2870, 2855, 1723, 1348, 1202, 1182, 1152, 1128, 1078, 1032 cm-1 ; MS (CI) m/e (% relative intensity) 183 (M+H+, 28), 85(100).
Reaction SMILES: [OH-].[K+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.CS(C)=O.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1([CH2:28]Br)[O:24][CH:23]([CH2:25][O:26][CH3:27])[CH2:22][O:21]1>O>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1([CH2:28][N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)[O:24][CH:23]([CH2:25][O:26][CH3:27])[CH2:22][O:21]1
Reactant: c1nc[nH]n1
Reactant: COCC1COC(CBr)(c2ccc(Cl)cc2Cl)O1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COCC1COC(Cn2cncn2)(c2ccc(Cl)cc2Cl)O1
Temperature: 80 °C

Procedure:
A mixture of 13 parts of powdered potassium hydroxide (85% purity), 15 parts of 1H-1,2,4-triazole and 165 parts of dimethylsulfoxide is heated at 80° C. for 1 hour. 58 Parts of 2-(2,4-dichlorophenyl)-2-(bromomethyl)-4-(methoxymethyl)-1,3-dioxolane are added and the whole is heated at 150° C. for 12 hours. The reaction mixture is poured onto 1000 parts of water. The product is extracted with 1,1'-oxybisethane. The extract is dried, filtered and evaporated. The residue is distilled under high vacuum yielding pure 1-[2-(2,4-dichlorophenyl)-4-(methoxymethyl)-1,3-dioxolan-2-ylmethyl]-1H-1,2,4-triazole; bp. 161°-168° C. at 0.01 mm. pressure. The product crystallizes on standing, yielding a solid having a melting point of 64°-74° C.