Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:24]([CH3:26])[CH3:25]>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[CH:7][N:8]2[CH:24]([CH3:26])[CH3:25])=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)C(F)(F)F
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(C(=O)C(F)(F)F)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
A solution of 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone in N,N-dimethylformamide (5 mL) was treated with potassium carbonate (698 mg, 5.05 mmol). The reaction was stirred at 25° C. for 15 min and then was treated with 2-iodopropane (0.30 mL, 3.03 mmol). This mixture was heated at 65° C. for 20 h. At this time, the reaction was cooled to 25° C., quenched with water (5 mL), and then partitioned between water (50 mL) and ethyl acetate (50 mL). This mixture was treated with a saturated aqueous sodium chloride solution (1×25 mL), shaken, and separated. The organic layer was then dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 3/1 hexanes/ethyl acetate) afforded 1-(6-chloro-1-isopropyl-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (483 mg, 83%) as a pale pink solid: mp 94-96° C.; EI-HRMS m/e calcd for C13H11ClF3NO (M+) 289.0481, found 289.0482.
Reaction SMILES: O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:12][CH:13]1[CH:38]2O[C:37]2([CH3:40])[CH:36]([OH:41])[CH2:35][C:33](=[O:34])[N:32]([CH3:42])[C:25]2=[C:26]([Cl:31])[C:27]([O:29][CH3:30])=[CH:28][C:23](=[CH:24]2)[CH2:22][C:21]([CH3:43])=[CH:20][CH:19]=[CH:18][CH:17]([O:44][CH3:45])[C:16]2([OH:50])[NH:46][C:47]([O:49][CH:14]1[CH2:15]2)=[O:48]>[Cl-].[Cl-].[Cl-].[Ti+3].O>[CH3:12][CH:13]1[CH:14]2[O:49][C:47]([NH:46][C:16]([OH:50])([CH2:15]2)[CH:17]([O:44][CH3:45])[CH:18]=[CH:19][CH:20]=[C:21]([CH3:43])[CH2:22][C:23]2=[CH:24][C:25](=[C:26]([Cl:31])[C:27]([O:29][CH3:30])=[CH:28]2)[N:32]([CH3:42])[C:33](=[O:34])[CH2:35][CH:36]([OH:41])[C:37]([CH3:40])=[CH:38]1)=[O:48]
Reactant: COc1cc2cc(c1Cl)N(C)C(=O)CC(O)C1(C)OC1C(C)C1CC(O)(NC(=O)O1)C(OC)C=CC=C(C)C2
Agent: [Ti+3]
Agent: COc1cc2cc(c1Cl)N(C)C(=O)CC(O)/C(C)=C/C(C)C1CC(O)(NC(=O)O1)C(OC)/C=C/C=C(\C)C2
Agent: COc1cc2cc(c1Cl)N(C)C(=O)CC(O)C1(C)OC1C(C)C1CC(O)(NC(=O)O1)C(OC)/C=C/C=C(\C)C2
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2cc(c1Cl)N(C)C(=O)CC(O)C(C)=CC(C)C1CC(O)(NC(=O)O1)C(OC)C=CC=C(C)C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 6 ml of dried tetrahydrofuran (THF) is added 321 mg of anhydrous titanium trichloride, and the mixture is stirred at room temperature in dry nitrogen atmosphere for 15 minutes while adding thereto portionwise 20 mg of lithium aluminum hydride (LAH). Thereafter, 50 mg of maytansinol is added, and the mixture is stirred at room temperature for about 30 minutes. Then, 15 ml of water is added, and the reaction mixture is extracted with chloroform, and the organic layer is washed with water and dried over anhydrous sodium sulfate. The chloroform is distilled off under reduced pressure, and the residue is purified by silica gel column chromatography [silica gel (Merck) Art 7736; solvent system: chloroform:methanol=100:1.5] to give 22 mg of 4,5-deoxymaytansinol. Yield=45.1%. Mass spectrum (m/e): 548 (M+), 530, 487.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([N:10]([CH2:13][C:14](=O)[CH3:15])[CH:11]=O)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:21].C(OCC)(=O)C.[OH-].[Na+]>C(O)(=O)C>[Br:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([N:10]2[CH:13]=[C:14]([CH3:15])[N:21]=[CH:11]2)=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: COc1nc(Br)ccc1N(C=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1nc(Br)ccc1-n1cnc(C)c1
Temperature: 140 °C
Yield: 14.5 %

Procedure:
A mixture of N-(6-bromo-2-methoxypyridin-3-yl)-N-(2-oxopropyl)formamide (7072 mg, 24.63 mmol) and ammonium acetate (8714 mg, 113 mmol) in 16 mL of acetic acid was heated at 140° C. for 1 h. The reaction mixture was cooled to rt and poured into a mixture of icewater and ethyl acetate. The pH of the resulting mixture was brought to pH 9 with a 50% aqueous sodium hydroxide solution. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuum and the residue was purified by column chromatography on silica gel to give 6-bromo-2-methoxy-3-(4-methyl-1H-imidazol-1-yl)pyridine (959.0 mg, 3.58 mmol, 14.52% yield) as brown solid. LC-MS (M+H)+=270.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@H:10]([OH:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:12][C@H:10]1[CH2:11][C@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:13])[CH2:9]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](O)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of tert-butyl(trans-3-hydroxycyclobutyl)carbamate (20.05 g, 107 mmol, MC09PH1559, Pharmacore) and triethylamine (22.34 mL, 161 mmol, Sigma-Aldrich Chemical Company, Inc.) in DCM (200 mL) was cooled to −30° C. and methanesulfonyl chloride (9.94 mL, 129 mmol, Sigma-Aldrich Chemical Company, Inc.) was added dropwise over 20 min period. The mixture was stirred at room temperature for 12 h, washed with 200 mL water, then 200 mL 10% aq. citric acid followed by brine, dried over Na2SO4 and evaporated to give the title compound (29 g, 109 mmol, 102% yield). It was used in the next step without further purification.
Reaction SMILES: [NH:1]1[CH2:9][C@H:7]([OH:8])[CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].C(N1CCOCC1)C.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[S:28](Cl)(=[O:30])=[O:29].C([O-])(O)=O.[Na+]>C[Si](C)(C)N[Si](C)(C)C.C1COCC1.CCOCC.C(O)C>[OH:8][C@H:7]1[CH2:9][N:1]([S:28]([C:19]2[CH:20]=[CH:21][C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]=2)(=[O:30])=[O:29])[C@H:2]([C:3]([OH:5])=[O:4])[CH2:6]1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: CCN1CCOCC1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOCC
Product: O=C(O)[C@@H]1C[C@@H](O)CN1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 120 °C
Reaction time: 50 h
Yield: 67.9 %

Procedure:
11 g (83.9 mmol) L-Hydroxyproline were dissolved in 110 ml hexamethyldisilazane and heated to 120° C. overnight, cooled to room temperature and evaporated. The oily residue was dissolved in 110 ml THF, 16.5 ml (79.7 mmol, 0.95 eq) N-ethyl-morpholine was added, followed by 18.25 g (79.7 mmol, 0.95 eq) 2-naphthalenesulfonyl chloride in 130 ml THF over a period of 60 min. The solution was stirred at RT for 50 h, 15 ml ethanol were added and the solution was stirred for 15 min. At that time 400 ml of Et2O and 250 ml of aqueous saturated NaHCO3 solution were added and the phases were separated. The aqueous layer was acidified and extracted with EtOAc, the combined organic layers were washed with brine, dried over MgSO4 and concentrated. 17.39 g (65%) (2S,4R)-4-hydroxy-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid isolated as yellow solid, mp 140° C., MS: 321 (MH+).
Reaction SMILES: COP([CH2:7][C:8](=[O:16])[C:9]([F:15])([F:14])[CH2:10][CH2:11][CH2:12][CH3:13])(=O)OC.O.[OH-].[Li+].[C:20]([O:23][C@@H:24]1[C@H:28]([CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[C@@H:27]([CH:39]=O)[C@H:26]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[CH2:25]1)(=[O:22])[CH3:21]>COC(C)(C)C.O>[C:20]([O:23][C@@H:24]1[C@H:28]([CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[C@@H:27](/[CH:39]=[CH:7]/[C:8](=[O:16])[C:9]([F:14])([F:15])[CH2:10][CH2:11][CH2:12][CH3:13])[C@H:26]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[CH2:25]1)(=[O:22])[CH3:21]
Reactant: COC(=O)CCC/C=C\C[C@@H]1[C@@H](C=O)[C@H](OC2CCCCO2)C[C@@H]1OC(C)=O
Reactant: CCCCC(F)(F)C(=O)CP(=O)(OC)OC
Agent: [Li+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: O
Product: CCCCC(F)(F)C(=O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 86.2 %

Procedure:
To a solution of dimethyl (3,3-difluoro-2-oxoheptyl)phosphonate (1) (1.816 g, 7.033 mmol) in t-butyl methyl ether (16 ml), lithium hydroxide monohydrate (0.271 g, 6.46 mmol) was added and the mixture was stirred for 2.25 hours at room temperature. A solution of methyl (Z)-7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyloxy)cyclopentyl]-5-heptenate (8) (1.554 g, 3.920 mmol) in t-butyl methyl ether (4.7 ml) and water (0.75 ml) were added thereto, and the mixed solution was heat refluxed for approximately 24 hours. After cooling to room temperature, water was added to the solution and the mixture was stirred, let to stand and then separated into two layers. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, sequentially washed with 3% aqueous sodium chloride and saturated aqueous sodium chloride, and dried with anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silysia BW-300SP: 47 g, ethyl acetate:hexane=1:4), to give methyl(Z)-7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]-5-heptenate (9) (1.787 g; 3.380 mmol; yield: 86.2%) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][N:14]1[CH2:20][C@H:19]3[C@H:16]([CH2:17][C@@H:18]3[N:21]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:15]1)=[N:9][C:8]([O:32][CH3:33])=[CH:7][CH:6]=2.NN>CCO>[F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][N:14]1[CH2:20][C@H:19]3[C@H:16]([CH2:17][C@@H:18]3[NH2:21])[CH2:15]1)=[N:9][C:8]([O:32][CH3:33])=[CH:7][CH:6]=2
Reactant: COc1ccc2ncc(F)c(CCN3C[C@H]4C[C@H](N5C(=O)c6ccccc6C5=O)[C@H]4C3)c2n1
Agent: NN
Solvent: CCO
Product: COc1ccc2ncc(F)c(CCN3C[C@H]4C[C@H](N)[C@H]4C3)c2n1
Reaction time: 2 h
Yield: 13.4 %

Procedure:
To a solution of (±)-2-((1S,5R,6S)-3-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-azabicyclo[3.2.0]hept-6-yl)-1H-isoindole-1,3(2H)-dione (324 mg, 0.73 mmol) in EtOH (36 mL) was added NH2NH2 (0.34 mL, 10.9 mmol) dropwise. After 2 h at 85° C., the solution was concentrated and the residue purified via column chromatography (silica, 2-5% MeOH in DCM (1% NH4OH)) yielding the title compound (31 mg, 13%) as a yellow oil: LC/MS (ES) m/e 317 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:2]=1.[F:13][C:14]([F:30])([F:29])[C:15]1[O:19][N:18]=[C:17]([C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=2)[C:23](O)=[O:24])[N:16]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:8][CH2:9][N:10]([C:23]([C:22]3[CH:26]=[CH:27][CH:28]=[C:20]([C:17]4[N:16]=[C:15]([C:14]([F:29])([F:13])[F:30])[O:19][N:18]=4)[CH:21]=3)=[O:24])[CH2:11][CH2:12]2)[CH:2]=1
Reactant: c1cncc(N2CCNCC2)c1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(c1cccc(-c2noc(C(F)(F)F)n2)c1)N1CCN(c2cccnc2)CC1
Yield: 47 %

Procedure:
This compound was synthesized from 1-(pyridin-3-yl)piperazine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (110 mg, yield 47%). 1H NMR (400 MHz, DMSO-d6) δ 8.32-8.31 (m, 1H), 8.18-8.15 (dt, J=6.7 Hz, 2.0 Hz, 1H), 8.08 (m, 1H), 8.03-8.02 (m, 1H), 7.76-7.71 (m, 2H), 7.36-7.33 (ddd, J=8.5 Hz, 3.0 Hz, 1.2 Hz, 1H), 7.25-7.22 (m, 1H), 3.81 (m, 2H), 3.50 (m, 2H), 3.21 (m, 4H). MS (ESI) m/z: Calculated for C19H16F3N6O2: 403.13. found: 404.2 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]=[CH2:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9].Cl.O.[OH-].[NH4+]>C(Cl)(Cl)Cl>[CH3:24][C:4]1[C:5]2([C:20]([O:22][CH3:23])=[O:21])[CH:6]3[CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:2]([CH3:1])([CH2:19][CH:18]2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=2)[N:3]=1
Reactant: C=Cc1ccccc1C1C(C(=O)OC)=C(C)NC(C)=C1C(=O)OC
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)C1C2c3ccccc3C3CC1(C)N=C(C)C32C(=O)OC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Into a solution of the Compound 2b (0.3 mmol) in dry chloroform (5 ml) was bubbled anhydrous hydrogen chloride. The resulting solution was stirred for 2.5 hours at ambient temperature. The reaction mixture was diluted chloroform (10 ml) and water (5 ml) and then neutralized with concentrated aqueous ammonium hydroxide. The organic phase was separated and the aqueous phase extracted with chloroform (2×20 ml). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo and the resulting yellow oil purified by flash chromatography on silica gel eluted with hexane:diethyl ether (1:2). The β-isomer had an Rf =0.4 and the α-isomer had an Rf =0.3.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9]([C:12]2[CH:19]=[CH:18][CH:17]=[C:16](F)[C:13]=2[C:14]#[N:15])(=[O:11])=[O:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[NH3:21].CCOC(C)=O>CO>[NH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[C:12]([S:9]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=2)(=[O:11])=[O:10])[C:13]=1[C:14]#[N:15]
Reactant: N
Reactant: Cc1cc(C)cc(S(=O)(=O)c2cccc(F)c2C#N)c1
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(S(=O)(=O)c2cccc(N)c2C#N)c1
Temperature: -78 °C
Reaction time: 24 h
Yield: 57.5 %

Procedure:
2-[(3,5-Dimethylphenyl)sulfonyl]-6-fluorobenzonitrile (Example 20) (0.5 g 1.7 mmol) was dissolved in 80 ml of methanol and chilled to -78° C. Condensed ammonia (20 ml, 15.4 g, 905 mmol) was added and the mixture was heated to150° C. in a sealed Parr bomb for 24 h. Chromatography on silica gel (flash; Hex/EtOAc 1:1) provided 0.28 g (56%) of 2-amino-6-[(3,5-dimethylphenyl)sulfonyl]benzonitrile: mp 208°-209° C.;; NMR (Me2SO-d6, 200 MHz) δ 2.36 (s, 6H), 6.59 (br s, 2H), 7.10 (apparent d, 1H), 7.3-7.4 (m, 2H) 7.54 (apparent d, 1H), 7.58 (m, 2H); mass spec (CI) M+ +1=287. Anal. Calc. for C15H14N2O2S: C, 62.92; H, 4.93; N: 9.78; S, 11.20. Found: C, 63.02; H, 4.98; N, 9.72; S, 11.12.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[C@H:10]([NH:20]C(OC(C)(C)C)=O)[CH2:11][C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:29]>C(OCC)(=O)C>[ClH:29].[CH2:1]([O:8][C:9](=[O:28])[C@H:10]([NH2:20])[CH2:11][C:12]([N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CC(=O)N1CCOCC1)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@H](CC(=O)N1CCOCC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
A solution of the title A compound, (2R)-(t-butyloxycarbonylamino)-4-morpholin-4-yl-4-oxobutyric acid benzyl ester (2.91 g, 7.42 mmol) in 50 mL of ethyl acetate is saturated with hydrogen chloride gas for 15 min. The reaction is sealed and stirred for 3 h at RT. The solvent is evaporated to afford 2.27 g (93%) of (2R)-amino-4-morpholin-4-yl-4-oxobutyric acid benzyl ester hydrochloride as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([CH3:14])([N+:11]([O-])=O)[CH3:10]>[Ni].C(O)C>[CH3:14][C:9]([NH2:11])([CH3:10])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: CC(C)(Cc1ccccc1Cl)[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: CC(C)(N)Cc1ccccc1Cl
Reaction time: 3.5 h

Procedure:
A mixture of Raney nickel (50% by weight in water; 2.3 g) and 1-(2-chlorophenyl)-2-methyl-2-nitropropane (2.35 g, 11 mmol) in ethanol (35 mL) was shaken under hydrogen gas (60 psig) for 3.5 h. The reaction mixture was then filtered, and the filtrate was rotary evaporated. This provided 2.3 g (110%) of α,α-dimethyl-2-chlorophenethylamine.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.O.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([N:23]4[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]4)=[N:7][N:6]3[CH:8]=2)=[CH:12][CH:13]=1
Reactant: CN1CCNCC1
Reactant: Fc1ccc(-c2cn3nc(Cl)ccc3n2)cc1
Solvent: O
Product: CN1CCN(c2ccc3nc(-c4ccc(F)cc4)cn3n2)CC1

Procedure:
After heating a suspension of 32 g (97.4 mmol) of 6-chloro-2-(4-fluorophenyl)imidazo[1,2-b]pyridazine (CAS No.: 2069-47-8) in 200 ml of 1-methylpiperazine at 160° C. for 16 hours, the mixture is poured into 1.5 L of water. The yellowish precipitate formed is separated out by filtration and rinsed with cold isopropanol and then with diisopropyl ether. 30 g of a beige-colored powder are thus isolated after drying under vacuum.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=1)[NH2:5].Cl[C:13]1[N:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][N:14]=1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:13]2[N:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=1
Reactant: Nc1cc(Br)cc([N+](=O)[O-])c1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cc(Br)cc(Nc2nccc(C(F)(F)F)n2)c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
was added to a solution of 3-bromo-5-nitroaniline (3.4 g, 15.7 mmol) and 2-chloro-4-(trifluoromethyl)pyrimidine) (2.27 mL, 18.80 mmol) in dioxane (78 ml) at room temperature, under nitrogen. The mixture became heterogeneous instantly and upon heating, a solution was obtained. The mixture was stirred at 100° C. for 18 hours then cooled to room temperature and concentrated under reduced pressure. Saturated sodium bicarbonate and dichloromethane were added, the organic phase was recovered using a phase separator and then concentrated under reduced pressure. The residue was washed in hexanes/ether and filtered to afford N-(3-bromo-5-nitrophenyl)-4-(trifluoromethyl)pyrimidin-2-amine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@@H:8]([CH3:25])[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[O:22][CH2:21][C@H:20]([CH2:23]O)[O:19][C:17]3=2)[CH:12]=[N:11]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(OS(C)(=O)=O)(=O)=O.[N-:43]=[N+:44]=[N-:45].[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.CS(C)=O>[C:1]([O:5][C:6](=[O:26])[NH:7][C@@H:8]([CH3:25])[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[O:22][CH2:21][C@H:20]([CH2:23][N:43]=[N+:44]=[N-:45])[O:19][C:17]3=2)[CH:12]=[N:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@@H](Cn1ncc2ccc3c(c21)O[C@@H](CO)CO3)NC(=O)OC(C)(C)C
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C[C@@H](Cn1ncc2ccc3c(c21)O[C@@H](CN=[N+]=[N-])CO3)NC(=O)OC(C)(C)C
Temperature: 90 °C
Yield: 89.5 %

Procedure:
To a 0° C. stirred solution of the alcohol from Step A (0.69 g, 1.87 mmol) in anhydrous tetrahydrofuran (30 mL) was added triethylamine (0.38 g, 0.52 mL, 3.7 mmol) and methanesulfonic anhydride (0.49 g, 2.81 mmol) under a nitrogen atmosphere. After 1 h the volatiles were evaporated. To the residue was added anhydrous DMSO (40 mL) and sodium azide (2.43 g, 37 mmol). The resulting mixture was heated at 90° C. for 1 h, cooled, mixed with a saturated aqueous solution of sodium bicarbonate (100 mL) and extracted with ethyl acetate (50 mL×3). Chromatography on silica eluting with a gradient of 0% to 25% ethyl acetate/hexane gave an oil (0.65 g, 88%), that solidified on standing. Crystallization from ethyl acetate/hexane gave a crystalline solid (0.48 g, 65%): mp 134-135° C. LCMS (+APCI) 395 (M+H).
Reaction SMILES: [CH3:1][C:2]([C:4]([O:6][CH2:7][CH2:8][N:9]1[CH:13]=[N:12]C=C1)=[O:5])=[CH2:3].C(OCCN1CCCC1=O)(=[O:18])C(C)=C>>[C:4]([O:6][CH2:7][CH2:8][NH:9][C:13]([NH2:12])=[O:18])(=[O:5])[C:2]([CH3:1])=[CH2:3]
Reactant: C=C(C)C(=O)OCCN1CCCC1=O
Reactant: C=C(C)C(=O)OCCn1ccnc1
Product: C=C(C)C(=O)OCCNC(N)=O

Procedure:
heterocyclic (meth)acrylates such as 2-(1-imidazolyl)ethyl (meth)acrylate, 2-(4-morpholinyl)ethyl (meth)acrylate and 1-(2-methacryloyloxyethyl)-2-pyrrolidone.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1([C:15]2[CH:16]=[CH:17][C:18](=[O:21])[NH:19][N:20]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl-].[NH4+]>C1COCC1.C1(C)C=CC=CC=1>[C:9]1([C:15]2[CH2:16][CH:17]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:18](=[O:21])[NH:19][N:20]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=c1ccc(-c2ccccc2)n[nH]1
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1NN=C(c2ccccc2)CC1c1ccccc1
Reaction time: 8 h
Yield: 50 %

Procedure:
135 ml (135 mmole) of a solution of phenylmagnesium bromide (1M) in THF was added to a hot suspension of 6-phenylpyridazinone compound 7.8 g (45 mmole) in dry toluene (50 ml). The mixture was refluxed for 8 h, left overnight at: ambient temperature, then decomposed with a saturated solution of ammonium chloride. The organic layer was separated, and the aqueous layer was extracted with 100 ml of ethyl acetate. The solvent was removed and the residue was crystallized from ethanol. The crystals were collected by filtering and dried over a medium frit sintered glass funnel in vacuo to give 5.6 g of white crystals. Yield was 50%, confirmed by ESI-MS. ESI-MS: m/z 250.1 (M+H+).
Reaction SMILES: I[CH2:2][Cl:3].C[O:5][C:6](=O)[C@@H:7]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=1.[Li+].CC([N-]C(C)C)C.C([Li])CCC>C1COCC1>[Cl:3][CH2:2][C:6](=[O:5])[C@@H:7]([NH:17][C:18](=[O:19])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH2:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=1
Reactant: COC(=O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C
Reactant: ClCI
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)C(=O)CCl
Reaction time: 0.5 h

Procedure:
ICH2Cl (3.54 g, 1.46 mL, 19.82 mmol, 1.25 equivalent) and THF (5 mL) are added to (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,5-difluorophenyl)propanoic acid methyl ester (II, EXAMPLE 1, 5 g, 15.86 mmol, 1 equivalent). The mixture is cooled to −78° and LDA (22.3 mL, 44.60 mmol, 2.25 equivalents, 2.0M) is added dropwise maintaining an internal temperature below −60°. Once the addition is complete, the contents are stirred for 30 min at −78° at which time n-butyllithium (15.3 mL, 19.82 mmol, 1.25 equivalents; 1.3M in hexanes) is added dropwise maintaining an internal temperature below about −60°. The reaction is stirred for 30 min then quenched into 0° hydrochloric acid (IN). Ethyl acetate is added and the phases are separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with saturated sodium bicarbonate, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, NMR (DMSO-d6) δ 7.47, 7.06-7.14, 4.78, 4.49, 3.20, 2.82 and 1.40; CMR (DMSO-d6) δ 200.87, 163.74, 161.20, 142.74, 112.80, 102.13, 79.04, 58.97, 47.72, 34.95 and 28.30.