Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16](CP(=O)(OCC)OCC)=[CH:15][C:14]=2OC)[N:3]=1.NC1C=CC([CH2:35][CH2:36][PH:37](=[O:41])[O:38][CH2:39][CH3:40])=CC=1>>[Cl:1][C:2]1[C:7]([C:8]([F:10])([F:9])[F:11])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:35][CH2:36][PH:37](=[O:41])[O:38][CH2:39][CH3:40])=[CH:15][CH:14]=2)[N:3]=1
Reactant: CCO[PH](=O)CCc1ccc(N)cc1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Product: CCO[PH](=O)CCc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Yield: 61 %

Procedure:
Prepared as described above for diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate using ethyl (4-aminobenzyl)methylphosphinate in place of diethyl (4-amino-3-methoxybenzyl)phosphonate. Following chromatography, the semi-pure product was crystallized from ethyl acetate to afford 1.1 g (61% yield) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.64 (s, 1H), 8.79 (d, J=0.51 Hz, 1H), 7.62 (d, J=8.34 Hz, 2H), 7.25 (dd, J=2.27, 8.59 Hz, 2H), 3.86-4.01 (m, 2H), 3.15 (d, J=17.68 Hz, 2H), 1.31 (d, J=13.64 Hz, 3H), 1.19 (t, J=6.95 Hz, 3H); MS (ES+): m/z: 396.0708 [MH+]. HPLC: tR=1.41 min (UPLC TOF MS: polar—3 min).
Reaction SMILES: [CH2:1]([S:8][C:9]([CH3:13])([CH3:12])[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.II.Br[C:18](=[CH2:23])[C:19]([O:21]C)=O.[CH2:24]1COCC1>[Zn]>[CH2:1]([S:8][C:9]([CH:10]1[O:11][C:19](=[O:21])[C:18](=[CH2:23])[CH2:24]1)([CH3:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(Br)C(=O)OC
Reactant: C1CCOC1
Reactant: CC(C)(C=O)SCc1ccccc1
Agent: Cl
Agent: II
Agent: [Zn]
Product: C=C1CC(C(C)(C)SCc2ccccc2)OC1=O
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of 2-benzylthio-2-methylpropionaldehyde (3.26 g) in THF (80 ml), zinc dust (2.56 g) activated with hydrochloric acid and a small amount of iodine were added. To the mixture methyl 2-bromoacrylate (3.00 g) dissolved in THF (20 ml) was added dropwise. The mixture was stirred for 3 hours under ultrasonic irradiation and filtrated by celite. To the filtrate ether was added. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The oily residue was purified by silica gel column chromatography to give 4.31 g (97%) of the titled compound.
Reaction SMILES: [CH3:1][CH:2]1[N:7]([C:8]2[C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=3)[CH2:6][CH2:5][O:4][CH2:3]1.[OH-].[Na+]>CO.O>[CH3:1][CH:2]1[N:7]([C:8]2[C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=3)[CH2:6][CH2:5][O:4][CH2:3]1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCOCC3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1COCCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccccc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(3-methylmorpholino)-2-phenylquinoxaline-6-carboxylate (45 mg, 0.12 mmol, 1.00 equiv) in methanol (10 mL). Then a solution of sodium hydroxide (25 mg, 0.62 mmol, 5.00 equiv) in water (2 mL) was added. The resulting solution was stirred for 2 hrs at 50° C. in an oil bath. The resulting mixture was concentrated in vacuo. The residue was diluted by 20 mL of water. The pH value of the aqueous solution was adjusted to 4-5 with aq. hydrogen chloride (1 mol/L). The resulting solids were collected by filtration. This resulted in 40 mg (90%) of 3-(3-methylmorpholino)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [NH2:1][C@:2]1([C:41]([OH:43])=[O:42])[C@@H:6]([CH2:7][CH2:8][CH2:9][B:10]2[O:14]C(C)(C)C(C)(C)[O:11]2)[CH2:5][N:4]([C:19](=[O:40])[C@H:20]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[NH:21]C(OC(C)(C)C)=O)[CH2:3]1.[ClH:44]>C1COCC1.O1CCOCC1.O>[ClH:44].[ClH:44].[NH2:1][C@:2]1([C:41]([OH:43])=[O:42])[C@@H:6]([CH2:7][CH2:8][CH2:9][B:10]([OH:14])[OH:11])[CH2:5][N:4]([C:19](=[O:40])[C@H:20]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:37])([F:39])[F:38])=[CH:32][CH:31]=2)[NH2:21])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)C(=O)N1C[C@H](CCCB2OC(C)(C)C(C)(C)O2)[C@](N)(C(=O)O)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: C1COCCO1
Product: N[C@@H](Cc1ccc(C(F)(F)F)cc1)C(=O)N1C[C@H](CCCB(O)O)[C@](N)(C(=O)O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of the crude (3R,4S)-3-amino-1-[N-(tert-butoxycarbonyl)-4-(trifluoromethyl)phenylalanyl]-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl]pyrrolidine-3-carboxylic acid (Step 2, 242 mg) in anhydrous THF (6 mL) under nitrogen was treated with 4 N HCl in 1,4-dioxane (6 mL). After stirring for 2 h at room temperature, 1M aqueous HCl (6 mL) was added and stirring was continued for an additional 1.5 h. The reaction mixture was diluted with water (15 mL) and washed successively with ethyl acetate (25 mL) and methylene chloride (25 mL). The aqueous phase was concentrated and the residue was purified by reverse phase HPLC. Product fractions (mixture of diastereomers) were pooled and concentrated. The residue was reconstituted in 1 M HCl and re-concentrated. The resulting residue was diluted with deionized water and lyophilized to give (3R,4S)-3-amino-4-[3-(dihydroxyboryl)propyl]-1-[4-(trifluoromethyl)phenylalanyl]-pyrrolidine-3-carboxylic acid dihydrochloride (mixture of two diastereomers, each a racemate) (43 mg, 12% overall for 3 steps) as a pale yellow amorphous solid. MS (ESI+) m/z 414 (M−H2O+H+), 396 (M−2H2O+H+); MS (ESI−) m/z 412 (M−H2O−H+).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:41])([F:40])[C:10]1[CH:11]=[C:12]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:13]([N:15]([CH:17]([CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1)[CH2:18][C:19](O)=[O:20])[CH3:16])=[O:14].[Cl:42][C:43]1[CH:49]=[CH:48][C:46]([NH2:47])=[C:45]([CH3:50])[CH:44]=1>C(Cl)Cl>[Cl:42][C:43]1[CH:49]=[CH:48][C:46]([NH:47][C:19](=[O:20])[CH2:18][CH:17]([N:15]([C:13](=[O:14])[C:12]2[CH:11]=[C:10]([C:9]([F:41])([F:8])[F:40])[CH:35]=[C:34]([C:36]([F:38])([F:39])[F:37])[CH:33]=2)[CH3:16])[CH2:22][C:23]2[CH:24]=[CH:25][C:30]3[C:31](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:32]=2)=[C:45]([CH3:50])[CH:44]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CC(=O)O)Cc1ccc2ccccc2c1
Reactant: Cc1cc(Cl)ccc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(Cl)ccc1NC(=O)CC(Cc1ccc2ccccc2c1)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
A solution of 0.055 ml (0.393 mmol) of triethylamine and 38 mg (0.0786 mmol) of 3-[N'-(3,5-bistrifluoromethyl-benzoyl)-N'-methyl-amino]-4-(2-naphthyl)-butanoic acid in 0.5 ml of methylene chloride and a solution of 33.3 mg of 1-propanephosphonic acid anhydride in 0.4 ml of methylene chloride are added in succession to 10.3 mg (0.0943 mmol) of 4-chloro-2-methylaniline and the mixture is left to stand at room temperature overnight (>16 hours). The reaction mixture is then washed with 0.5 ml of a 1N aqueous potassium carbonate solution. The aqueous phase is extracted with a further 0.8 ml of methylene chloride. The combined organic phases are concentrated by evaporation in a vacuum centrifuge. The title compound is obtained in the form of a white foam. TLC: methylene chloride/acetone (7:3) Rf =0.48.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH3:6])([O-:3])=O.C1(N=C=O)C=CC=CC=1.[C:16]([C:18]12[CH2:25][CH2:24][CH2:23][N:22]1[CH2:21][CH2:20][CH2:19]2)#[CH:17]>C1C=CC=CC=1>[CH2:5]([C:4]1[CH:17]=[C:16]([C:18]23[CH2:25][CH2:24][CH2:23][N:22]2[CH2:21][CH2:20][CH2:19]3)[O:3][N:1]=1)[CH3:6]
Reactant: CCC[N+](=O)[O-]
Reactant: C#CC12CCCN1CCC2
Solvent: c1ccccc1
Solvent: O=C=Nc1ccccc1
Product: CCc1cc(C23CCCN2CCC3)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
Nitropropane (0.475 mL, 5.29 mmol) and phenylisocyanate (1.0 mL, 9.5 mmol) were dissolved in benzene (10 mL) and added to a flask containing 7a-ethynyl-hexahydro-1H-pyrrolizine (358 mg, 2.65 mmol, from step 13a). The solution was stirred at ambient temperature for 1 hour and at reflux for 5 hours. The mixture was cooled, filtered, concentrated and diluted with EtOAc. The solution was extracted with 6N HCl. The aqueous phase was made basic with 15% NaOH and extracted with methylene chloride. The organic extracts were combined, dried (MgSO4) and concentrated. The residue was residue was chromatographed (silica gel; CHCl3 /MeOH, 98:2) to afford an amber oil (274 mg, 50%). 1H NMR (CDCl3, 300 MHz) δ1.25 (t, J=7.5 Hz, 3H), 1.75-1.92 (m, 6H), 2.15-2.25 (m, 2H), 2.60-2.69 (m, 4H), 3.13-3.20 (m, 2H), 5.98 (s, 1H); MS (CI/NH3) m/z: 207 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][C:12]([CH3:18])([OH:17])[C:13]([F:16])([F:15])[F:14].[CH3:19][S:20]([C:23]1[C:31]2[C:26](=[CH:27][N:28]=[CH:29][CH:30]=2)[NH:25][N:24]=1)(=[O:22])=[O:21].CS([C:36]1[C:44]2C(=CC=CC=2)NN=1)(=O)=O>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[N:9]([CH2:10][CH2:11][C:12]([CH3:18])([OH:17])[C:13]([F:16])([F:14])[F:15])[C:36]([CH2:44][N:25]3[C:26]4=[CH:27][N:28]=[CH:29][CH:30]=[C:31]4[C:23]([S:20]([CH3:19])(=[O:22])=[O:21])=[N:24]3)=[N:1][C:2]=2[CH:7]=1
Reactant: CC(O)(CCNc1ccc(Cl)cc1N)C(F)(F)F
Reactant: CS(=O)(=O)c1n[nH]c2cnccc12
Reactant: CS(=O)(=O)c1n[nH]c2ccccc12
Product: CC(O)(CCn1c(Cn2nc(S(C)(=O)=O)c3ccncc32)nc2cc(Cl)ccc21)C(F)(F)F

Procedure:
The title compound was prepared in analogy to Example 2-1 by using 4-[(2-amino-4-chlorophenyl)amino]-1,1,1-trifluoro-2-methylbutan-2-ol and 3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine instead of 4-chloro-N—((R)-1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-benzene-1,2-diamine and 3-methanesulfonyl-1H-indazole.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][OH:21])[O:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](N1C=CN=C1)([N:24]1C=CN=[CH:25]1)=[O:23].CN>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][O:21][C:22](=[O:23])[NH:24][CH3:25])[O:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OCc1cc(-c2ccc(OCc3ccccc3)cc2)no1
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)OCc1cc(-c2ccc(OCc3ccccc3)cc2)no1

Procedure:
0.5 g of the compound [3-(4-benzyloxy-phenyl)-isoxazol-5-yl]-methanol in Example 1 was dissolved in 10 ml of THF, to which solution was added 0.49 g (1.7 equivalents) of 1,1′-carbonyldiimidazole. The consumption of all the reactants was confirmed by TLC, and 2 equivalents of methyl amine were added to the reaction solution. 2 hours later, the solvent was distilled off under reduced pressure, 50 ml of a 1N—HCl aqueous solution was placed in the reactants, and the mixture was extracted three times with 30 ml of ethyl acetate. An obtained organic layer was distilled under reduced pressure, followed by column chromatography to obtain methyl-carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester as a desired compound.
Reaction SMILES: O=[C:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14](=[O:26])[NH:15][C@H:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17]2)[CH2:3]1.[NH2:27][C:28]1[CH:37]=[C:36]2[C:31]([CH2:32][C@@H:33]([C:45](=[O:57])[NH:46][C@H:47]3[C:56]4[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=4)[CH2:50][CH2:49][CH2:48]3)[N:34]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:35]2)=[CH:30][CH:29]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].Cl>ClCCCl.CCOC(C)=O>[C:10]([O:9][C:7]([N:5]1[C@H:4]([C:14](=[O:26])[NH:15][C@H:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17]2)[CH2:3][C@H:2]([NH:27][C:28]2[CH:37]=[C:36]3[C:31]([CH2:32][C@@H:33]([C:45](=[O:57])[NH:46][C@H:47]4[C:56]5[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=5)[CH2:50][CH2:49][CH2:48]4)[N:34]([C:38]([O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:39])[CH2:35]3)=[CH:30][CH:29]=2)[CH2:6]1)=[O:8])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(N)ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1Cc2cc(N[C@H]3C[C@@H](C(=O)N[C@@H]4CCCc5ccccc54)N(C(=O)OC(C)(C)C)C3)ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.8 %

Procedure:
To a solution of (S)-tert-butyl 4-oxo-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidine-1-carboxylate (73 mg, 0.20 mmol) in DCE (2.0 mL) was added (S)-tert-butyl 7-amino-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (86 mg, 0.20 mmol) and AcOH (12 μL, 0.20 mmol). Na(OAc)3BH (78 mg, 0.37 mmol) was then added, and the resulting reaction mixture was stirred at room temperature for 4 h. Additional AcOH (12 μL, 0.20 mmol) and Na(OAc)3BH (78 mg, 0.37 mmol) were added, and stirring was continued overnight at room temperature. The reaction mixture was poured into a separatory funnel containing 1N HCl and EtOAc. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (151 mg, 97%) as a colorless oil. MS (ESI+) m/z 764.5 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[C:12]([N:19]1[CH2:24][C@@H:23]([CH3:25])[NH:22][CH2:21][C@@H:20]1[CH3:26])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C.O>[C:15]([O:14][C:12]([N:19]1[CH2:24][C@@H:23]([CH3:25])[N:22]([C:2]2[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=2)[CH2:21][C@@H:20]1[CH3:26])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])cnc1N1C[C@H](C)N(C(=O)OC(C)(C)C)C[C@H]1C
Temperature: 80 °C
Reaction time: 20 h

Procedure:
Dissolve 2-chloro-3-methyl-5-nitropyridine (310 mg, 1.82 mmol, 1.0 equiv) and N—BOC-trans-2,5-dimethylpiperazine (397 mg, 2.0 mmol, 1.1 equiv) in 5 mL of anhydrous DMF, add potassium carbonate (251 mg, 1.82 mmol, 1.0 equiv) and stir the mixture for 20 hours at 80° C. Pour the solution in a 1:1 v/v mixture of EtOAc and iced water. Extract the aqueous phase with EtOAc (2×20 mL) and wash the combined organic layers with water (3×20 mL) and saturated aq. sodium chloride (30 mL). Dry the organic solution over sodium sulfate and concentrate under reduced pressure to obtained a crude rac-(trans)-2,5-dimethyl-4-(3-methyl-5-nitro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester. MS(ES+): m/z=251.2 (M+H).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[N:12]=[C:11]([C:13](=[O:15])[CH3:14])[CH:10]=[CH:9][CH:8]=1)(C)C.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH2:26][CH2:27][CH3:28])[C:21](=[O:29])[C:20]2=[O:30].CNC>CO>[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH2:26][CH2:27][CH3:28])[C:21](=[O:29])[C:20]2([CH2:14][C:13]([C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([C:6]#[CH:5])[N:12]=1)=[O:15])[OH:30]
Reactant: CCCN1C(=O)C(=O)c2cc(Cl)ccc21
Reactant: CC(=O)c1cccc(C#C[Si](C)(C)C)n1
Agent: CNC
Solvent: CO
Product: C#Cc1cccc(C(=O)CC2(O)C(=O)N(CCC)c3ccc(Cl)cc32)n1
Temperature: 80 °C

Procedure:
To a clean biotage vial equipped with a stir bar was added 1-(6-((trimethylsilyl)ethynyl)pyridin-2-yl)ethanone (0.0255 grams, 0.12 mmol), 5-chloro-1-propylindoline-2,3-dione, (0.015 grams, 0.067 mmol). This was taken up in 0.2 mL of methanol (purchased from Fisher Scientific). Dimethylamine (2.5 μL 40% in water purchased from Fisher Scientific) was then added and the solution heated in a Biotage initiator microwave for ten minutes at 80° C. Once complete, the reaction was concentrated using a Buchi rotoevaporator and purified using a Teledyne ISCO with silica gel (hexane, ethyl acetate gradient). Yield, 40%. 1H-NMR δ 8.06 (dd, 1H), 7.89 (t, 1H), 7.69 (dd, 1H), 7.35 (d, 1H), 7.29 (dd, 1H), 6.80 (d, 1H), 6.02 (s, 1H), 3.88 (d, 1H), 3.62 (m, 3H), 3.25 (s, 1H), 1.71 (m, 2H), (0.97 (t, 3H). calculated mass for C20H17ClN2O3, 368.09. Observed, 369.0 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]([CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].O.[OH-].[Li+].[ClH:24].CCOCC>C1COCC1.O>[ClH:24].[C:1]([C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)CCc1cncn1Cc1ccc(C#N)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: N#Cc1ccc(Cn2cncc2CCC(=O)O)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of the methyl ester 5 (1.10 g) in 10 mL of THF and 5 mL of water was added lithium hydroxide monohydrate (172 mg). After two hours, the reaction was cooled to 0° C., and a 1 M solution of HCl/ether (8.2 mL) was added. The solution was concentrated and dried in vacuo next to P2O5 to provide the product 6 as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([NH:23][C:24]([N:26]3[CH2:29][CH:28]([NH:30]C(=O)OC(C)(C)C)[CH2:27]3)=[O:25])=[CH:21][N:22]=2)[N:19]=1.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>C(Cl)Cl>[F:41][C:40]([F:43])([F:42])[C:38]([OH:44])=[O:39].[NH2:30][CH:28]1[CH2:29][N:26]([C:24]([NH:23][C:20]2[N:18]3[N:19]=[C:14]([N:10]4[CH2:11][CH2:12][CH2:13][C@@H:9]4[C:3]4[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=4[F:1])[CH:15]=[CH:16][C:17]3=[N:22][CH:21]=2)=[O:25])[CH2:27]1
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)Nc2cnc3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)nn23)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CN(C(=O)Nc2cnc3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)nn23)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(R)-tert-butyl 1-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-ylcarbamoyl)azetidin-3-ylcarbamate (Example 14; 10 mg, 0.019 mmol) was dissolved in 0.5 mL 50% TFA in DCM and stirred at ambient temperature for 2 hours. The reaction is concentrated, treated with ether, and concentrated again to yield the final product salt form as a white solid. MS (apci) m/z=414.2 (M+H).
Reaction SMILES: [F:1][C:2]([F:55])([F:54])[C:3]1[CH:4]=[C:5]([CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=1)[CH2:6][N:7]([C@H:26]1[CH2:32][CH2:31][CH2:30][N:29]([CH2:33][CH:34]2[CH2:36][CH2:35]2)[C:28]2[C:37]([CH3:46])=[C:38]([C:42]([F:45])([F:44])[F:43])[C:39]([CH3:41])=[CH:40][C:27]1=2)[C:8]1[N:9]=[N:10][N:11]([CH2:13][CH2:14][N:15]2C(=O)C3C(=CC=CC=3)C2=O)[N:12]=1.O.NN>CO>[NH2:15][CH2:14][CH2:13][N:11]1[N:10]=[N:9][C:8]([N:7]([CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:54])[F:55])[CH:49]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:47]=2)[C@H:26]2[CH2:32][CH2:31][CH2:30][N:29]([CH2:33][CH:34]3[CH2:35][CH2:36]3)[C:28]3[C:37]([CH3:46])=[C:38]([C:42]([F:44])([F:45])[F:43])[C:39]([CH3:41])=[CH:40][C:27]2=3)=[N:12]1
Reactant: Cc1cc2c(c(C)c1C(F)(F)F)N(CC1CC1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(CCN2C(=O)c3ccccc3C2=O)n1
Agent: NN
Solvent: CO
Solvent: O
Product: Cc1cc2c(c(C)c1C(F)(F)F)N(CC1CC1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(CCN)n1
Temperature: 25 °C
Yield: 98.3 %

Procedure:
Heat the mixture of (S)-2-(2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(1-cyclopropylmethyl-7,9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amino]-tetrazol-2-yl}-ethyl)-isoindole-1,3-dione (0.175 g, 0.224 mmol) and hydrazine hydrate (0.1 ml) in methanol (2.0 mL) at 60° C. overnight. Cool down to room temperature. Remove the precipitate by filtration and evaporate the solvent to provide the title compound (0.143 g, 98%). MS (ES+): 650 (M+H).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([N:16]2[CH2:21][CH2:20][O:19][C@:18]([CH2:30][CH2:31][OH:32])([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[CH3:51][C:52]1[CH:57]=[CH:56][C:55]([S:58](Cl)(=[O:60])=[O:59])=[CH:54][CH:53]=1.Cl>C(Cl)Cl.O>[CH3:51][C:52]1[CH:57]=[CH:56][C:55]([S:58]([O:32][CH2:31][CH2:30][C@:18]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[O:19][CH2:20][CH2:21][N:16]([C:14](=[O:15])[CH2:13][C:5]3[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:4]=3)[CH2:17]2)(=[O:60])=[O:59])=[CH:54][CH:53]=1
Reactant: O=C(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCO[C@](CCO)(c2ccc(Cl)c(Cl)c2)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC[C@@]2(c3ccc(Cl)c(Cl)c3)CN(C(=O)Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CCO2)cc1
Temperature: 2.5 °C
Yield: 60.3 %

Procedure:
To a solution of (2R)-2-[4-{[3,5-bis(trifluoromethyl)phenyl]acetyl}-2-(3,4-dichlorophenyl)morpholin-2-yl]ethanol obtained in Reference Example 1 (3.0 g, 5.7 mmol) in methylene chloride (30 ml) were added dimethylaminopyridine (0.07 g, 0.57 mmol) and triethylamine (1.2 ml, 8.5 mmol) under a nitrogen stream, the resulting mixture was cooled to 0-5° C., and then a solution of 4-methylbenzenesulfonyl chloride (1.3 g, 6.8 mmol) in methylene chloride (10 ml) was further added dropwise at below 10° C. with stirring. After the resulting mixture was stirred at room temperature for 8 hours, to the reaction mixture were added water (30 ml) and concentrated hydrochloric acid (1 ml), and the resulting mixture was partitioned. The separated organic layer was washed with water (30 ml) and evaporated to dryness. The residue obtained was purified by chromatography on a silica gel column and then crystallized from a mixed solvent of toluene (7 ml) and methylcyclohexane (35 ml) under ice-cooling to afford the title compound [2.3 g, yield: 60.3%] as a colorless crystalline solid.
Reaction SMILES: [SH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:3]([OH:5])=O.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=O)[CH:16]=1.[CH3:23][N:24]([CH2:26][CH2:27][NH2:28])[CH3:25]>C1(C)C=CC=CC=1>[CH3:23][N:24]([CH3:25])[CH2:26][CH2:27][N:28]1[C:3](=[O:5])[CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[S:1][CH:21]1[C:17]1[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=1
Reactant: CN(C)CCN
Reactant: O=Cc1cccnc1
Reactant: CCCCCCCCCC(S)C(=O)O
Solvent: Cc1ccccc1
Product: CCCCCCCCCC1SC(c2cccnc2)N(CCN(C)C)C1=O
Reaction time: 2 h
Yield: 91.4 %

Procedure:
2-Mercaptoundecanoic acid (5.0 g, 22.9 mmol), pyridine-3-aldehyde (2.16 ml, 22.9 mmol), and N-dimethylaminoethylamine (2.51 ml, 22.9 mmol) were dissolved in toluene (100 ml), and subjected to azeotropic dehydration for 2 hours. The solvent was removed from the product mixture by evaporation under reduced pressure. The residue was purified by column chromatography, giving 3-(2-dimethylaminoethyl)-5-(n-nonyl)-2-(3-pyridyl)thiazolidin-4-one (7.9 g, 91% yield). IR (CHCl3) [cm-1 ]; 2850, 1660, 1577, 1408.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[CH2:13][C:14]([O-:16])=[O:15].[Na+].N.[NH2-].[Na+]>>[C:10]([CH:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:13][C:14]([OH:16])=[O:15])#[N:11]
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Reactant: O=C([O-])CCl
Agent: N
Agent: [NH2-]
Agent: [Na+]
Product: N#CC(CC(=O)O)c1ccc(Cl)c(Cl)c1

Procedure:
A mixture of 93 g (0.50 mol) of 3,4-dichlorophenylacetonitrile and 64 g (0.55 mol) of sodium chloroacetate is reacted for 4 hours at -33° C. in 500 ml of liquid ammonia, in the presence of 21 g (0.54 mol) of sodium amide. After evaporation of the ammonia, the residue is taken up with water and then with isopropyl ether and is acidified to pH<3 with hydrochloric acid. The organic phase is washed with water to pH>3, separated off by decantation, dried over magnesium sulfate and concentrated to dryness. The residue is solidified in toluene and characterized by proton NMR. M.p.=106° C.