Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OS([O-])=O.[Na+].[CH:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=1[NH2:25])[C:18]([O:20][CH3:21])=[O:19].O>C(O)C>[C:7]1([C:6]2[NH:25][C:24]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=3[N:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: O=Cc1ccccc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc2[nH]c(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
An aqueous solution of NaHSO3 (21.0 mL, 40% in water) was treated benzaldehyde (2.00 mL, 20.0 mmol) and stirred at ambient temperature for 1 h. A solution of methyl 3,4-diaminobenzoate (3.32 g, 20.0 mmol) in ethanol (15.0 mL) was added and the solution was heated to reflux for 6 h. Upon cooling, the solution was poured into water and the resultant precipitate was collected by filtration, washed with water, and dried in vacuo to provide the title compound as a grey solid (4.90 g; 97%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.85 (br. s., 1H) 8.35 (s, 1H) 8.11 (d, J=2.0 Hz, 1H) 8.10 (d, J=4.0 Hz, 1H) 7.97 (dd, J=8.6, 1.5 Hz, 1H) 7.63 (d, J=5.8 Hz, 1H) 7.46 (d, J=2.3 Hz, 2H) 7.45 (dd, J=5.5, 4.0 Hz, 1H) 3.94 (s, 3H). MS (ES+) m/e 253 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=O)=[CH:4][CH:3]=1.CC[O-].[Na+].[NH2:17][CH:18]([CH2:22][C:23]1[C:24](=[O:33])[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:19]([OH:21])=[O:20]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:17][CH:18]([CH2:22][C:23]2[C:24](=[O:33])[NH:25][C:26]3[C:31]([CH:32]=2)=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:19]([OH:21])=[O:20])=[O:8])=[CH:11][CH:12]=1
Reactant: NC(Cc1cc2ccccc2[nH]c1=O)C(=O)O
Reactant: CCOC(=O)c1ccc(Cl)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(NC(Cc1cc2ccccc2[nH]c1=O)C(=O)O)c1ccc(Cl)cc1
Reaction time: 6 h
Yield: 9 %

Procedure:
In 100 ml of ethanol, 1.66 g of ethyl p-chlorobenzate, 0.5 g of sodium ethylate and 2.09 g of 2-amino-3-(2-quinolon-3-yl)propionic acid were added and the whole mixture was placed in an autoclave. The reaction was carried out under 110 atmospheric pressure at 140°-150° C. for 6 hours. After completion of the reaction, the reaction mixture was cooled and concentrated under a reduced pressure. The residue was dissolved in 200 ml of chloroform, washed with 1%-potassium carbonate aqueous solution, a diluted hydrochloric acid and water in this order, then the chloroform layer was dried with sodium sulfate. The solvent was removed by distillation, the residue was recrystallized from ethanol-water to obtain 300 mg of 2-(4-chlorobenzoylamino)-3-(2-quinolon-3-yl)propionic acid in the form of white powdery product.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]#[CH:22])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>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>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]#[C:22][C:2]2[N:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Brc1ncccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(C#Cc2ncccn2)CC1
Reaction time: 8 h
Yield: 8 %

Procedure:
To a suspension of 2-bromopyrimidine (175 mg, 1.1 mmols), dichlorobis(triphenylphosphine)palladium(II) (35 mg, 0.05 mmols) and Cul (10 mg, 0.05 mmols) was added a solution of 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester (209 mg, 1 mmol). The mixture was stirred overnight, filtered through Celite, concentrated. The residue was partitioned between ethyl acetate and water, organic layer was isolated, dried (MgSO4), and concentrated. The residue was chromatographed on silica gel eluting with ethyl acetate in hexanes (1:1) to give un-reacted 2-bromopyrimidine (130 mg), then the title compound (23 mg). LCMS m/e (288, M+H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[N:4]=[CH:5][C:6]([NH:9][C@H:10]2[CH2:14][CH2:13][CH2:12][C@@H:11]2[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[N:7][CH:8]=1.[Br:25]N1C(=O)CCC1=O>C(Cl)Cl.C(#N)C>[Br:25][C:5]1[C:6]([NH:9][C@H:10]2[CH2:14][CH2:13][CH2:12][C@@H:11]2[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[N:7][CH:8]=[C:3]([C:2]([F:1])([F:23])[F:24])[N:4]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)nc1Br
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of tert-butyl N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]carbamate (11.61 g, 33.5 mmol) in DCM (70 ml) and acetonitrile (35 ml) at 0° C. under was added 1-bromopyrrolidine-2,5-dione (12.53 g, 70.4 mmol). The reaction was allowed to warm to room temperature and stirred for 20 hours. The mixture was concentrated in vacuo and then purified by column chromatography (silica, 0-50% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4](Cl)[CH:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:12][CH:11]=1.Cl.C(OCC)(=O)C.CCCCCC>C(OCCO)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:12][CH:11]=2)[CH:3]=1
Reactant: Nc1ccc(NC(=O)OCc2ccccc2)cc1
Reactant: Nc1cc(Cl)ncn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCCO
Solvent: CCCCCC
Product: Nc1cc(Nc2ccc(NC(=O)OCc3ccccc3)cc2)ncn1
Temperature: 120 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
6-Amino-4-chloropyrimidine (259 mg) was dissolved in 2-ethoxyethanol (10 ml), and then benzyl N-(4-aminophenyl)carbamate (533 mg) and 2 N HCl (2 ml) were added thereto, followed by stirring at 120° C. overnight. The reaction mixture was cooled down to room temperature, and partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (eluent; ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated to give a residue, to which ethyl acetate-hexane was then added to precipitate crystals. The solid was filtered, and dried under aeration to provide the titled compound (313.1 mg, 47%) as opaline crystals.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][C:12](O)=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1.C(Cl)(=O)C([Cl:24])=O.CN(C)C=O>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]([CH2:11][C:12]([Cl:24])=[O:13])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)C[C@H](CC(=O)O)c1ccc2c(c1)OCO2
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H](CC(=O)Cl)c1ccc2c(c1)OCO2
Reaction time: 24 h

Procedure:
(S)-3-(1,3-benzodioxol-5-yl)-5-ethoxy-5-oxopentanoic acid (2.01, 7.2 mmol) was dissolved in methylene chloride (50 mL) at O° C. under argon. An excess of oxalyl chloride (3 mL) was added along with a drop of dimethylformamide (catalyst). The reaction mixture was stirred 24 hours and concentrated to a crude brown oil. Yield=2.23 g (>100%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[C:12]([Br:14])[CH:11]=[C:10]2[C:5]=1[NH:6][C:7](=[O:16])[C:8](=[O:15])[NH:9]2.[CH2:17]([O:19][C:20](=[O:26])/[CH:21]=[CH:22]/[C:23](O)=[O:24])[CH3:18].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl>CN(C)C=O.O.C(N(CC)CC)C>[CH2:17]([O:19][C:20](=[O:26])[CH:21]=[CH:22][C:23](=[O:24])[NH:2][CH2:3][C:4]1[CH:13]=[C:12]([Br:14])[CH:11]=[C:10]2[C:5]=1[NH:6][C:7](=[O:16])[C:8](=[O:15])[NH:9]2)[CH3:18]
Reactant: CCOC(=O)/C=C/C(=O)O
Reactant: NCc1cc(Br)cc2[nH]c(=O)c(=O)[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C=CC(=O)NCc1cc(Br)cc2[nH]c(=O)c(=O)[nH]c12
Reaction time: 0.25 h

Procedure:
351 mg (1 mmol) of 5-aminomethyl-7-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline hydrochloride, (Example 2) 217 mg (1.5 equiv.) of fumaric acid monoethyl ester, 0.210 ml of triethylamine, 383 mg (2 equiv.) of N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride and 270 mg (2 equiv.) of 1-hydroxy-benzotriazole are stirred at 20° C. in dried dimethylformamide for 18 hours. The mixture is poured into 700 ml of water and 3 ml of 1 N hydrochloric acid and stirred for 15 minutes. The solid is filtered off, washed with water and dried.
Reaction SMILES: [H-].[Na+].[NH:3]([C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]#[C:19][CH3:20])[N:13]=[CH:12][N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH2:22][CH3:23].[Cl-].[NH4+]>O1CCCC1>[CH2:22]([N:3]([C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]#[C:19][CH3:20])[N:13]=[CH:12][N:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:23]
Reactant: CCI
Reactant: CC#CCOc1cc(Nc2ccccc2)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(N(CC)c2ccccc2)ncn1
Temperature: 25 °C
Yield: 71.6 %

Procedure:
In 0.8 ml of tetrahydrofuran was suspended 0.04 g of sodium hydride (60% in oil), to which 0.6 ml of a tetrahydrofuran solution containing 0.15 g of 4-anilino-6-(2-butynyloxy)pyrimidine were slowly added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 20 minutes, to which 0.4 ml of a tetrahydrofuran solution containing 0.12 g of iodoethane was slowly added dropwise at room temperature, followed by stirring for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.12 g of 4-(N-ethyl-N-phenylamino)-6-(2-butynyloxy)pyrimidine (the present compound (81)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:13][CH2:12][C:11](=[O:14])[N:10]([C@@H:15]([CH2:20][CH3:21])[C:16](OC)=[O:17])[C@@H:9]2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Li+].CO>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:9]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[N:10]([C@@H:15]([CH2:20][CH3:21])[CH2:16][OH:17])[C:11](=[O:14])[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](C(=O)OC)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: CCOCC
Product: CC[C@@H](CO)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To an ice-cooled solution of 48.5 g (115 mmol) of (S)-methyl 2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)butanoate (Example 185, Step A) in ethyl ether (850 mL) was added 5.96 g (90%, 246 mmol) of lithium borohydride. The resulting light yellow solution was stirred at 0° C. for 3 h, and then MeOH (2.5 mL) and more ethyl ether (100 mL) were added. Gas evolution was observed upon the addition of MeOH. After 40 min, the reaction was quenched by cautious addition of 1 N HCl until bubbling subsided. The mixture was extracted with EtOAc (2×), and the combined organic layers were washed with saturated aqueous sodium chloride (1×). The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated to afford the title compound as a white foam. The crude product was used directly in the next step without further purification.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1)[C:26](Cl)=[O:27]>C(Cl)Cl>[CH3:33][O:32][C:30]1[CH:29]=[C:25]([CH:24]=[C:23]([O:22][CH3:21])[CH:31]=1)[C:26]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)=[O:27]
Reactant: NCCCSc1ccncc1
Reactant: COc1cc(OC)cc(C(=O)Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OC)cc(C(=O)NCCCSc2ccncc2)c1
Yield: 87.7 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.77 ml (19.8 mmol) of triethylamine in 40 ml of methylene chloride was added 995 mg (4.96 mmol) of 3,5-dimethoxybenzoyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 1.21 g of the desired compound (87.7%, pale yellow powder), mp: 110.0°-111.0° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[CH2:12]([O:14][C:15](=[O:29])[C:16]([C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:17]OCC)[CH3:13]>C1(C)C=CC=CC=1>[CH2:12]([O:14][C:15](=[O:29])[C:16]([C:21](=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[CH:17][NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=1[C:2]([F:10])([F:11])[F:1])[CH3:13]
Reactant: Nc1ccccc1C(F)(F)F
Reactant: CCOC=C(C(=O)OCC)C(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNc1ccccc1C(F)(F)F)C(=O)c1ccccc1
Reaction time: 18 h
Yield: 82.2 %

Procedure:
A mixture of 2-(trifluoromethyl)aniline(4.6 g, 28.8 mmol) and 2-benzoyl-3-ethoxy-acrylic acid ethyl ester 7.2 g, 28.8 mmol) in toluene (125 ml) was heated to reflux. After 18 hr, the reaction was cooled, concentrated and purified by column chromatography (eluent 10% EtOAc/hexane) to give 2-benzoyl-3-(2-trifluoromethyl-phenylamino)-acrylic acid ethyl ester (8.6 g, Yield=82%); MS (ESI) m/z 364(M+H)+; Anal Calcd for C19H16F3NO3: C, 62.81; H, 4.44; N, 3.85. Found: C, 62.87; H, 4.21; N, 3.76.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CN(C)CCCN(C)C.CS(Cl)(=O)=O.[NH2:36][C:37]1[CH:46]=[CH:45][C:40]([C:41]([O:43][CH3:44])=[O:42])=[CH:39][CH:38]=1.C(N(CC)C(C)C)(C)C>O.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([NH:36][C:37]3[CH:38]=[CH:39][C:40]([C:41]([O:43][CH3:44])=[O:42])=[CH:45][CH:46]=3)[CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: OC(c1ccc(-c2ccc(Cl)cc2)cc1)C1CCCCC1
Agent: CN(C)CCCN(C)C
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(NC(c2ccc(-c3ccc(Cl)cc3)cc2)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Under a nitrogen atmosphere, to a mixture of (4′-chlorobiphenyl-4-yl)(cyclohexyl)methanol obtained in step B, N,N,N′,N′-tetramethyl-1,3-propanediamine (0.265 mL) and toluene (4.432 mL) was added methanesulfonyl chloride (0.124 mL) at 0° C., and the reaction mixture was stirred at room temperature for 4 hr. To the reaction mixture were added methyl 4-aminobenzoate (301 mg) and N,N-diisopropylethylamine (0.464 mL) at room temperature, and the mixture was stirred at 100° C. overnight. To the reaction mixture was added water at room temperature, the mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (382.4 mg).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:8][C:7]1=[O:20].S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C.O>[O:20]=[C:7]1[CH2:8][C:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])([C:10]([O:12][CH2:13][CH3:14])=[O:11])[NH:6]1
Reactant: CCOC(=O)C1(C(=O)OCC)CC(=O)N1Cc1ccc(OC)cc1OC
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C1(C(=O)OCC)CC(=O)N1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
1(b) 17.4 g of diethyl 1-(2,4-dimethoxybenzyl)-2-oxoazetidine-4,4-dicarboxylate (prepared as described above) were dissolved in a mixture of 350 ml of acetonitrile and 350 ml of water. 11.2 g of potassium persulfate and 37.4 g of dibasic potassium phosphate were then added to the resulting solution, and the mixture was stirred at 65° C. for 1 hour. At the end of this time, insoluble materials were filtered off and the filtrate was freed from the solvent by evaporation under reduced pressure. The residue was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, with an aqueous solution of sodium bicarbonate and with a saturated aqueous solution of sodium chloride, in that order. The solvent was then removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, eluted with a 1: 2 by volume mixture of ethyl acetate and benzene, to give 5.72 g of diethyl 2-oxoazetidine-4,4-dicarboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([CH2:15][N:16]=[N+:17]=[N-:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:22]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH3:22])[CH:10]([CH2:15][N:16]=[N+:17]=[N-:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(O)C(CN=[N+]=[N-])C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1CCN(C(=O)OC(C)(C)C)CC1CN=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 76 %

Procedure:
To a stirred solution of 3-azidomethyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (2 mmol, 0.512 g; Example 100) in DMF (5 mL) at 0° C. was added NaH (0.1 g, 60% dispersion in mineral oil) and continued stirring at 0° C. for 20 min. To this was Iodomethane (0.5 mL) and stirred at room temperature for 20 min. The volatiles were removed under reduced pressure, residue was dissolved in ethyl acetate (10 mL), washed with water, separated the organic layer, dried and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography to get 3-azidomethyl-4-methoxy-piperidine-1-carboxylic acid tert-butyl ester (0.41 g, 76% yield).
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:7][NH:6][CH2:5][C@H:4]1[NH:8][C:9]1[C:10]2[N:11]([CH:18]=[C:19]([C:21]3[CH:22]=[N:23][C:24]([CH2:27][NH:28][C:29](=[O:33])[CH2:30][O:31][CH3:32])=[CH:25][CH:26]=3)[CH:20]=2)[N:12]=[CH:13][C:14]=1[C:15]([NH2:17])=[O:16])[CH3:2].[C:34]([C:36]1([C:39](O)=[O:40])[CH2:38][CH2:37]1)#[N:35].CN([P+](ON1N=NC2C1=CC=CC=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:34]([C:36]1([C:39]([N:6]2[CH2:7][C@H:3]([CH2:1][CH3:2])[C@H:4]([NH:8][C:9]3[C:10]4[N:11]([CH:18]=[C:19]([C:21]5[CH:22]=[N:23][C:24]([CH2:27][NH:28][C:29](=[O:33])[CH2:30][O:31][CH3:32])=[CH:25][CH:26]=5)[CH:20]=4)[N:12]=[CH:13][C:14]=3[C:15]([NH2:17])=[O:16])[CH2:5]2)=[O:40])[CH2:38][CH2:37]1)#[N:35]
Reactant: CC[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(-c3ccc(CNC(=O)COC)nc3)cc12
Reactant: N#CC1(C(=O)O)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@H]1CN(C(=O)C2(C#N)CC2)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3ccc(CNC(=O)COC)nc3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
A mixture of 4-(((3S,4S)-4-ethylpyrrolidin-3-yl)amino)-6-(6-((2-methoxyacetamido)methyl)pyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide, 2hydroiodide (26 mg, 0.037 mmol), 1-cyanocyclopropanecarboxylic acid (12.25 mg, 0.110 mmol), BOP-reagent (48.8 mg, 0.110 mmol) and Hunig's Base (0.045 mL, 0.257 mmol) in DMF (1 mL) was stirred at rt overnight. The reaction mixture was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 5-100% B over 15 minutes, then a 7-minute hold at 100% B; Flow: 25 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (6 mg, 0.011 mmol, 30% yield). 1H NMR (500 MHz, METHANOL-d4) δ 8.78 (dd, J=11.9, 2.0 Hz, 1H), 8.19-8.10 (m, 1H), 8.07-7.90 (m, 2H), 7.38 (dd, J=8.2, 3.7 Hz, 1H), 7.20-7.06 (m, 1H), 5.05 (t, J=4.2 Hz, 0.5H), 4.91 (t, J=4.5 Hz, 0.5H), 4.57 (s, 2H), 4.37-4.25 (m, 1.5H), 4.18 (d, J=11.4 Hz, 0.5H), 3.97 (s, 2H), 3.94-3.75 (m, 1.5H), 3.49-3.37 (m, 3.5H), 2.69-2.59 (m, 0.5H), 2.58-2.46 (m, 0.5H), 1.83-1.32 (m, 6H), 1.08-0.96 (m, 3H) fractional peaks are due to the presence of amide rotomers. MS (ES+) m/z: 545.1 (M+H); LC retention time: 1.15 min (analytical LCMS Method H).
Reaction SMILES: [NH2:1]/[C:2](/OCC)=[CH:3]\[C:4](=O)[C:5]([F:8])([F:7])[F:6].Cl.[F:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[CH:17][CH:16]=1.C(N(CC)CC)C>>[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:2]([NH2:1])=[CH:3][C:4]([C:5]([F:6])([F:7])[F:8])=[N:22]2)=[CH:17][CH:16]=1
Reactant: CCO/C(N)=C/C(=O)C(F)(F)F
Reactant: NNc1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: Nc1cc(C(F)(F)F)nn1-c1ccc(F)cc1
Yield: 63.8 %

Procedure:
According to the procedure described in Example 161A Step 3, using (E)-4-amino-4-ethoxy-1,1,1-trifluorobut-3-en-2-one (2.747 g, 15 mmol), (4-fluorophenyl)hydrazine hydrochloride (2.439 g, 15 mmol), and triethylamine (2.03 g, 20 mmol) at 95° C. for 8 hours, which was purified by silica gel chromatography with 5-25% EtOAc/hexane as eluants to afford 1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-amine as solid (2.346 g, 64%). 1H NMR (300 MHz, CDCl3) 67.55 (m, 2H), 7.20 (m, 2H), 5.87 (s, 1H), 3.87 (br, 2H); LC-MS (ESI) m/z 246 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:35]=[CH:36][C:37]=1[Cl:38])[CH2:6][CH:7]1[C:16]2[CH:15]=[C:14]([O:17][CH2:18][CH2:19][NH:20][S:21]([C:24]3[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=3)(=[O:23])=[O:22])[CH:13]=[CH:12][C:11]=2[CH2:10][CH2:9][CH:8]1[N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.IC.[C:41](=O)([O-])[O-].[Cs+].[Cs+].O>C(#N)C.C(Cl)Cl>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([CH:35]=[CH:36][C:37]=1[Cl:38])[CH2:6][CH:7]1[C:16]2[CH:15]=[C:14]([O:17][CH2:18][CH2:19][N:20]([CH3:41])[S:21]([C:24]3[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=3)(=[O:22])=[O:23])[CH:13]=[CH:12][C:11]=2[CH2:10][CH2:9][CH:8]1[N:30]1[CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: O=C([O-])[O-]
Reactant: Cn1cc(S(=O)(=O)NCCOc2ccc3c(c2)C(Cc2ccc(Cl)c(Cl)c2)C(N2CCCC2)CC3)cn1
Agent: Cl
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: CN(CCOc1ccc2c(c1)C(Cc1ccc(Cl)c(Cl)c1)C(N1CCCC1)CC2)S(=O)(=O)c1cnn(C)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
N-(2-(8-(3,4-Dichlorobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethyl)-1-methyl-1H-pyrazole-4-sulfonamide hydrochloride (41 mg, 0.068 mmol, Example 91, iodomethane (11.6 mg, 0.082 mmol), caesium carbonate (49.0 mg, 0.150 mmol) were dissolved in acetonitrile (3 ml) and stirred for 1 h at 100° C. in the microwave. After addition of another iodomethane (11.6 mg, 0.082 mmol) and caesium carbonate (49.0 mg, 0.150 mmol) it was stirred for another 1 h at 100° C. in the microwave. Water and CH2Cl2 were added, the organic phase separated and the aqueous phase extracted with CH2Cl2. The combined organic layers were washed with saturated NaCl solution, dried over Na2SO4, and concentrated to afford a residue that was purified by flash chromatography (silica gel, MeOH/CH2Cl2 3:97→5:95). The white solid product (42 mg, 38%) was transferred to an HCl salt and precipitated from diisopropyl ether. ESI-MS [M+H+]=577