Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=O)[CH2:7][CH2:8][C@@:9]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:14][C:13](=[O:15])[N:12]([C@H:16]([C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=2)[CH3:17])[CH2:11][CH2:10]1)(=[O:3])[CH3:2].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[Br:24][C:21]1[CH:20]=[CH:19][C:18]([C@@H:16]([N:12]2[CH2:11][CH2:10][C@:9]([CH2:8][CH2:7][C:6]3[O:3][C:1]([CH3:2])=[N:4][N:5]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:14][C:13]2=[O:15])[CH3:17])=[CH:23][CH:22]=1
Reactant: CC(=O)NNC(=O)CC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: Cc1nnc(CC[C@]2(c3ccccc3)CCN([C@@H](C)c3ccc(Br)cc3)C(=O)O2)o1
Yield: 58.7 %

Procedure:
To a solution of N′-acetyl-3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanehydrazide (0.1 g, 0.21 mmol) in THF (2 mL) was added Burgess Reagent (75 mg, 0.315 mmol). The sealed vial was irradiated in the microwave at 100° C. for 15 min. The mixture was extracted with EtOAc (3×30 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC to afford (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)-6-phenyl-1,3-oxazinan-2-one (58 mg, yield: 59%). 1H NMR (CDCl3): δ1.49-1.51 (m, 3H), 2.23-2.26 (m, 2H), 2.30-2.33 (m, 2H), 2.42 (s, 3H), 2.43-2.45 (m, 1H), 2.49-2.54 (m, 1H), 2.87-2.91 (m, 1H), 3.06-3.09 (m, 1H), 5.61-5.63 (m, 1H), 6.76-6.78 (d, 2H), 7.20-7.22 (m, 2H), 7.26-7.33 (m, 2H), 7.35-7.37 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][OH:8])=[C:5]([CH3:9])[O:4][N:3]=1>ClCCl.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[C:6]([CH:7]=[O:8])=[C:5]([CH3:9])[O:4][N:3]=1
Reactant: Cc1noc(C)c1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1noc(C)c1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
Manganese dioxide (5.48 g, 62.9 mmol) and dichloromethane (20 mL) were added to a solution of 3,5-dimethylisoxazole-4-methanol (prepared according to the literature procedure: Saucy, G.; Scott, J. W. U.S. Pat. No. 3,984,428 Oct. 5, 1976; 1.00 g, 7.9 mmol) in dichloromethane (25 mL). The mixture was stirred at room temperature overnight, then filtered through Celite®, evaporated under reduced pressure and the residual material was chromatographed over silica gel (10% ethyl acetate/hexanes) to give 3,5-dimethylisoxazole-4-carboxaldehyde (365 mg, 37% yield) as a colorless solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:23]=[C:24]([CH:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1.Cl.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:26]4[CH:27]=[CH:22][CH:23]=[C:24]([CH:28]5[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]5)[CH:25]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CN1CCC(c2cccc(Br)c2)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Agent: Cl
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCC(c2cccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)c2)CC1

Procedure:
4-(3-Bromo-phenyl)-1-methyl-piperidine hydrochloride was prepared from 4-(3-bromo-phenyl)-piperidine; hydrochloride (1.0 g, 3.6 mmol) in a manner analogous to Step 34c. The reaction product was isolated as a white solid (0.43 g, 41%) and was used without further purification. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 10.52 (s, 1H), 7.47-7.41 (m, 2H), 7.37-7.21 (m, 2H), 3.52-3.41 (m, 2H), 3.10-2.95 (m, 2H), 2.85-2.78 (m, 1H), 2.75 (s, 3H), 2.15-2.78 (m, 4H). 61b) [8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(1-methyl-piperidin-4-yl)-phenyl]-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 4-(3-bromo-phenyl)-1-methyl-piperidine; hydrochloride (90.0 mg, 0.310 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (30.0 mg, 0.0549 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a tan solid (0.031 g, 26%). MP=208-210° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.51 (d, J=6.5 Hz, 1H), 8.08 (d, J=8.3 Hz, 2H), 8.10 (d, J=7.3 Hz, 2H), 7.66 (d, J=6.6 Hz, 1H), 7.55 (s, 1H), 7.38 (d, J=8.7 Hz, 1H), 7.31-7.25 (m, 1H), 7.02 (t, J=7.4 Hz, 1H), 6.91-6.85 (m, 2H), 3.10 (s, 3H), 3.01 (d, J=10.9 Hz, 2H), 2.57-2.45 (m, 1H), 2.35 (S, 3H), 2.11-2.03 (m, 2H), 1.92-1.83 (m, 4H). MS=462 (MH)+.
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[C:6]([CH3:13])[CH:7]=[C:8]([CH3:12])[C:9]=2[OH:11])[CH2:4][CH2:3]1.[C:14]([C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:25]=1[OH:26])[CH:21]=O)([CH3:17])([CH3:16])[CH3:15].[BH4-].[Na+].Cl.C([O-])(=O)C.[Na+]>C(O)C.O>[C:27]([C:24]1[CH:23]=[C:20]([CH:19]=[C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:25]=1[OH:26])[CH2:21][NH:1][CH:2]1[C:10]2[C:5](=[C:6]([CH3:13])[CH:7]=[C:8]([CH3:12])[C:9]=2[OH:11])[CH2:4][CH2:3]1)([CH3:29])([CH3:30])[CH3:28]
Reactant: Cc1cc(C)c2c(c1O)C(N)CC2
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH4-]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c2c(c1O)C(NCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.77 Grams of 1-amino-7-hydroxy-4,6-dimethylindane and 50 ml of ethanol solution containing 2.57 g of 3,5-di-tert-butyl-4-hydroxybenzaldehyde were stirred together at a room temperature for 2 hours. Then sodium borohydride solution was added gradually by small portions to the reaction mixture under an ice-cooling condition. The reaction mixture was further stirred at a room temperature for 2 hours, then was acidified by adding hydrochloric acid. Then the reaction mixture was concentrated to dryness by evaporating the solvent under a reduced pressure. To the residue obtained was added 100 ml of water, and further added an aqueous solution of sodium acetate to adjust the pH of the solution to about pH=8, then extracted with 100 ml of ethyl acetate. The extract was washed with water, dried with anhydrous magnesium sulfate, concentrated to dryness by evaporating the solvent under a reduced pressure. The residue obtained was dissolved in 50 ml of ethanol, and the pH of the solution was adjusted by adding ethanol saturated with hydrogen chloride gas to about pH=3, then the solution was concentrated to dryness by evaporating the solvent under a reduced pressure. The residue obtained was recrystallized from ether-n-hexane to obtain 0.77 g of 1-(3,5-di-tert-butyl-4-hydroxybenzyl)amino-4,6-dimethyl-7-hydroxyindane in the form of colorless needle-like crystals. Melting point: 154°-155° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.Cl.Cl[CH2:21][C:22]1[C:23]([NH:35][CH2:36][CH3:37])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH3:33])=[C:27]([F:34])[CH:26]=2.[Li+].[OH-]>C1COCC1>[CH2:36]([NH:35][C:23]1[C:22]([CH2:21][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]=2[OH:18])=[CH:31][C:30]2[C:25](=[CH:26][C:27]([F:34])=[C:28]([O:32][CH3:33])[CH:29]=2)[N:24]=1)[CH3:37]
Reactant: CCNc1nc2cc(F)c(OC)cc2cc1CCl
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCc1nc(O)c(Cc2cc3cc(OC)c(F)cc3nc2NCC)c2cc(OC)c(OC)cc12
Temperature: 155 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35142 (184 mg, 0.744 mmol) in THF (15 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 3-(chloromethyl)-N-ethyl-7-fluoro-6-methoxyquinolin-2-amine hydrochloride SMA 44096 (227 mg, 0.744 mmol) at RT followed by a 2 N aq. LiOH solution (0.75 mL, 1.50 mmol) and the mixture was stirred at 155° C. for 1.5 h under microwave irradiation. The microwave vial was then cooled in an ice bath and the solid was filtered, washed with cold THF (20 mL) and taken up in CH2Cl2:MeOH=9:1 (50 mL). The organic solution was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5) followed by a second purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 95:5) gave 83 mg of 4-((2-(ethylamino)-7-fluoro-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (5 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (1.0 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 4-((2-(ethylamino)-7-fluoro-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol dihydrochloride 70 as a yellow solid (96 mg, 23% yield).
Reaction SMILES: [Br:1]Br.C([O-])(=O)C.[K+].[CH2:8]([N:12]1[C:16]([CH2:17][CH2:18][S:19]([CH2:22][CH2:23][CH3:24])(=[O:21])=[O:20])=[CH:15][C:14]([C:25]#[N:26])=[N:13]1)[CH2:9][CH2:10][CH3:11].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:1][C:15]1[C:14]([C:25]#[N:26])=[N:13][N:12]([CH2:8][CH2:9][CH2:10][CH3:11])[C:16]=1[CH2:17][CH2:18][S:19]([CH2:22][CH2:23][CH3:24])(=[O:21])=[O:20]
Reactant: CCCCn1nc(C#N)cc1CCS(=O)(=O)CCC
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(=O)O
Product: CCCCn1nc(C#N)c(Br)c1CCS(=O)(=O)CCC
Temperature: 25 °C
Yield: 58.7 %

Procedure:
Bromine (0.8 mL, 14.7 mmol) was added dropwise to a stirred solution of potassium acetate (2.00 g, 20.1 mmol) and 1-butyl-5-[2-(propylsulfonyl)ethyl]-1H-pyrazole-3-carbonitrile (3.80 g, 13.4 mmol) in acetic acid (27 mL). The reaction was stirred at ambient temperature, then was concentrated under reduced pressure to afford a solid. Saturated aqueous sodium bicarbonate was added to the solid until the mixture was pH 9. The mixture was extracted with dichloromethane (2×50 mL). The organic layers were combined and concentrated under reduced pressure to afford a brown oil. The crude product was purified by flash chromatography (silica gel, elution with 40% ethyl acetate in hexanes) to yield 2.85 g of 4-bromo-1-butyl-5-[2-(propylsulfonyl)ethyl]-1H-pyrazole-3-carbonitrile as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[OH:27])#[N:20].[Cl-].[NH4+]>CN(C)C=O>[CH2:9]([O:8][C:6]1[CH:7]=[C:2]([O:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:19]#[N:20])[N:3]=[CH:4][N:5]=1)[C:10]#[C:11][CH3:12]
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: N#Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1cc(Oc2ccccc2C#N)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 68.8 %

Procedure:
To 2 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-butynyloxy)pyrimidine, 0.23 g of potassium carbonate and 0.16 g of 2-cyanophenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.2 g of 4-(2-butynyloxy)-6-(2-cyanophenoxy) pyrimidine (the present compound (42)).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:10]2[O:11][CH:12]=[CH:13][N:14]=2)[CH:7]=[C:6]([NH2:15])[CH:5]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:10]2[O:11][CH:12]=[CH:13][N:14]=2)[CH:7]=[C:6]([NH:15][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH:5]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)c1cc(N)cc(-c2ncco2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1cc(NC(=O)OCc2ccccc2)cc(-c2ncco2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 10.3 g (47.2 mmol) of 3-amino-5-oxazol-2-yl-benzoic acid methyl ester, 25 g of anhydrous sodium carbonate and 7.69 ml (51.9 mmol) of benzyl chloroformate is stirred for 16 h at rt and filtered. The filtrate is concentrated, and the residue is chromatographed on silica gel (EtOAc/hexane 1:2) to yield the product in the form of colorless crystals.
Reaction SMILES: CN(C)C=O.[CH3:6][C:7]1([CH3:18])[CH2:12][CH2:11][C:10]2[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:9]=2[O:8]1.[H-].[Na+].Cl[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][N:23]=1>O>[CH3:6][C:7]1([CH3:18])[CH2:12][CH2:11][C:10]2[CH:13]=[CH:14][C:15]([O:17][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][N:23]=3)=[CH:16][C:9]=2[O:8]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC1(C)CCc2ccc(O)cc2O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CCc2ccc(Oc3ccc([N+](=O)[O-])cn3)cc2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
Five milliliters of an N,N-dimethylformamide solution of 1.5 g of 2,3-dihydro-2,2-dimethyl-7-hydroxy-4H-1-benzopyran synthesized by the method of Referential Example 19 was added dropwise to a mixture of 0.35 g of sodium hydride and 4 ml of N,N-dimethylformamide. The mixture was stirred at room temperature for 0.5 hour, and 6 ml of an N,N-dimethylformamide solution of 2-chloro-5-nitropyridine (1.3 g) was added to the resulting reddish orange solution, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into 100 ml of water, and extracted with 100 ml of ethyl acetate. The extract was dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography to give 2.1 g (yield 84%) of the desired product as a yellow liquid.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:15]([OH:17])=[O:16])[CH2:13][OH:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH2:18](N(CC)CC)C.COS(OC)(=O)=O.O>CN(C)C=O>[CH3:18][O:16][C:15](=[O:17])[C@H:12]([CH2:13][OH:14])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CCN(CC)CC
Reactant: O=C(N[C@@H](CO)C(=O)O)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-CBZ-L-serine (25 g) was dissolved in 100 ml of dry N,N-dimethylformamide at 0° C. under argon. Triethylamine (2 e.g., 30 ml) and dimethylsulfate (20 ml) were added. The contents of the vessel were stirred overnight at room temperature and then poured into 500 ml of water and extracted with ethyl acetate (3×200 ml). The organic layer was washed with water and brine and dried with sodium sulfate. Rotary evaporation afforded an oil which crystallized after silica gel chromatography in pure ethyl ether. The structure of the product, N-CBZ-L-serine methyl ester, was confirmed by NMR spectroscopy.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19]([OH:21])=O)=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[N:26](C=O)C.C(Cl)(=O)C(Cl)=O.N>C1COCC1>[N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19]([NH2:26])=[O:21])=[N:14][N:15]=3)[N:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cccc(-c2nnc3ccc(N4CCCCC4)nn23)c1
Reactant: CN(C)C=O
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: NC(=O)c1cccc(-c2nnc3ccc(N4CCCCC4)nn23)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution mixture of 3-[6-(piperidin-1-yl)-1,2,4-triazolo[4,3-b]pyridazine-3-yl]benzoic acid (430 mg), a catalytic amount of DMF and THF (10 ml), oxalyl chloride (0.44 ml) was added with cooling in ice, and the mixture was stirred at room temperature for 2 hours and then ammonia gas was passed with cooling in ice for 15 minutes. The reaction solution was concentrated under reduced pressure, and the resultant residue was combined with chloroform:methanol (10:1), and then insoluble materials were filtered off. The filtrate was concentrated under reduced pressure, and the resultant crude crystals were recrystallized from ethanol to obtain 3-[6-(piperidin-1-yl)-1,2,4-triazolo[4,3-b]pyridazin-3-yl]benzamide (242 mg) as slightly tan crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:5]1.C(N(CC)CC)C.[S:22](Cl)([CH3:25])(=[O:24])=[O:23]>O1CCCC1>[CH3:25][S:22]([O:1][CH2:2][CH2:3][C:4]1([NH:7][C:8]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:14])[CH2:5][CH2:6]1)(=[O:24])=[O:23]
Reactant: CC(C)(C)OC(=O)NC1(CCO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1(CCOS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a cooled solution of tert-butyl [1-(2-hydroxyethyl)cyclopropyl]carbamate (8.0 g, 0.04 mol) and triethylamine (12.14 g) in anhydrous tetrahydrofuran (120 mL) at −20° C. was added a solution of mesyl chloride (17.8 g) in anhydrous tetrahydrofuran (30 mL). The resulting mixture was allowed to warm to room temperature and stirred at this temperature for 2 hours. The resulting mixture was poured into ice-water (50 mL) and the separated organic layer was washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo. The residue was triturated with petroleum ether and filtered to give 9.5 g of the pure product as an orange solid (yield was 95%).
Reaction SMILES: [CH2:1]([N:3]([CH2:53][CH3:54])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([CH:30]=[CH:31][CH:32]=2)[C:16]([N:18]([CH2:20][CH2:21][N:22]2[CH2:26][CH2:25][CH2:24][C@H:23]2[C:27]([OH:29])=O)[CH3:19])=[O:17])=[O:12])=[C:6]([C:33]2[CH:38]=[C:37]([C:39](=[O:52])[NH:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([F:51])([F:50])[F:49])[CH:43]=3)[CH:36]=[CH:35][N:34]=2)[CH:5]=1)[CH3:2].[CH3:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][O:68][CH2:69][CH2:70][O:71][CH2:72][CH2:73][O:74][CH2:75][CH2:76][O:77][CH2:78][CH2:79][NH2:80].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][O:68][CH2:69][CH2:70][O:71][CH2:72][CH2:73][O:74][CH2:75][CH2:76][O:77][CH2:78][CH2:79][NH:80][C:27]([C@@H:23]1[CH2:24][CH2:25][CH2:26][N:22]1[CH2:21][CH2:20][N:18]([CH3:19])[C:16](=[O:17])[C:15]1[CH:30]=[CH:31][CH:32]=[C:13]([C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([N:3]([CH2:53][CH3:54])[CH2:1][CH3:2])=[CH:5][C:6]=2[C:33]2[CH:38]=[C:37]([C:39](=[O:52])[NH:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([F:51])([F:50])[F:49])[CH:43]=3)[CH:36]=[CH:35][N:34]=2)=[O:12])[CH:14]=1)=[O:29]
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCN3CCC[C@H]3C(=O)O)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: COCCOCCOCCOCCOCCOCCOCCOCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCN3CCC[C@H]3C(=O)NCCOCCOCCOCCOCCOCCOCCOCCOC)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
To a mixture of (S)-1-(2-(3-((4-(diethylamino)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)-N-methylbenzamido)ethyl)pyrrolidine-2-carboxylic acid (1.32 mmol, 1.12 g), 2,5,8,11,14,17,20,23-octaoxapentacosan-25-amine (1.38 mmol, 530 mg) and DIEA (9.21 mmol, 1.19 g) in DMF (4 mL) was added HATU (1.45 mmol, 0.551 g). The mixture was stirred at 60° C. for 1 h and purified by prep. HPLC to give a syrup (1.18 g, 62%). MS (ES, m/z): 1110.42 [M+H]+.
Reaction SMILES: COS(O)(=O)=O.B(OC)(OC)OC.CO.C[C:17]([O:19][CH2:20][C:21]1[CH2:30][S:29][C@@H:24]2[C@H:25]([NH2:28])[C:26](=[O:27])[N:23]2[C:22]=1[C:31]([OH:33])=[O:32])=O>CCCCCC.O1CCOCC1>[NH2:28][CH:25]1[C:26](=[O:27])[N:23]2[C:22]([C:31]([OH:33])=[O:32])=[C:21]([CH2:20][O:19][CH3:17])[CH2:30][S:29][C@H:24]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: COB(OC)OC
Agent: COS(=O)(=O)O
Solvent: CO
Solvent: CCCCCC
Solvent: C1COCCO1
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: -15 °C
Reaction time: 5 h
Yield: 85.8 %

Procedure:
20.28 g of a methanolic solution of methoxysulfonic acid (prepared as described in Preparation 2), 2.20 g of trimethyl borate and 1.15 g of methanol were added to 3.5 ml of dioxane. The mixture was cooled to -15° C., and a suspended slurry of 2.74 g of 7-ACA in 15 ml of hexane were added thereto, followed by stirring at -6° C. for 5 hours. After completion of the reaction, the reaction mixture was treated following the procedures described in Example 2 to give 2.11 g (yield 86%) of the desired compound at a high purity.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14](Cl)=[N:13][CH:12]=1.[CH2:19]([NH2:22])[CH2:20][NH2:21]>>[NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([NH:21][CH2:20][CH2:19][NH2:22])=[N:13][CH:12]=1
Reactant: Nc1cc(F)ccc1NC(=O)c1ccc(Cl)nc1
Reactant: NCCN
Product: NCCNc1ccc(C(=O)Nc2ccc(F)cc2N)cn1
Yield: 61 %

Procedure:
N-(2-Amino-4-fluorophenyl)-6-chloronicotinamide (266 mg, 1 mmol) and 5 ml of ethylenediamine were heated to 80° C. for 3 hours. The excess ethylenediamine was removed under vacuum. To the residue was added 5 ml of 0.20 M NaOH. The mixture was extracted with 100 ml of ethyl acetate. The ethyl acetate was removed under vacuum to give the title compound (176 mg, 61% yield) as a brown solid. LC-MS (m/z) 290 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:15][C@H:14]2[C@H:10]([CH2:11][CH:12]([CH3:16])[CH2:13]2)[C@H:9]1[CH2:17][NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:16][CH:12]1[CH2:11][C@H:10]2[C@H:14]([CH2:15][NH:8][C@@H:9]2[CH2:17][NH:18][C:19](=[O:24])[C:20]([F:23])([F:21])[F:22])[CH2:13]1
Reactant: CC1C[C@H]2CN(C(=O)OC(C)(C)C)[C@H](CNC(=O)C(F)(F)F)[C@H]2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1C[C@H]2CN[C@H](CNC(=O)C(F)(F)F)[C@H]2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold (0° C.) solution of (1S,2S,5R)-2-[(2,2,2-trifluoro-acetylamino)-methyl]-7-methyl-3-aza-bicyclo[3.3.0]-octane-3-carboxylic acid tert.-butyl ester (1.51 g) in DCM (13 mL) was slowly added TFA (3.31 mL, 10 eq). The reaction mixture was allowed to warm at RT and stirred overnight. Solvent and excess of TFA were removed in vacuo and the product was used for the next step without further purification.