Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:6](Br)=[C:5]([Br:8])[NH:4][N:3]=1.[CH2:9]([O:11]CC)C.C([Li])CCC.CN(C)C=O>O>[Br:8][C:5]1[C:6]([CH:9]=[O:11])=[C:2]([Br:1])[NH:3][N:4]=1
Reactant: CCOCC
Reactant: Brc1n[nH]c(Br)c1Br
Agent: [Li]CCCC
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1c(Br)n[nH]c1Br
Temperature: -75 °C
Reaction time: 1.5 h

Procedure:
81.7 g (0.268 mol) of 3,4,5-tribromopyrazole are introduced with stirring into 1500 cm3 of diethyl ether at a temperature in the region of 20° C. and under an argon atmosphere. The mixture is cooled to a temperature in the region of −78° C. and 335 cm3 (0.536 mol) of n-butyllithium at 1.6 mol/l are then added dropwise over 3 hours 15 minutes. The reaction mixture is stirred for 1.5 hours at a temperature in the region of −75° C., followed by dropwise addition of 100 cm3 (1.34 mol) of dimethylformamide, while keeping the temperature below −70° C. Stirring is continued for 2 hours at a temperature in the region of −75° C., and then for 15 hours at a temperature in the region of 20° C. The reaction medium is then cooled in an ice bath and 1000 cm3 of water are added. After separation of the phases by settling, the aqueous phase is extracted with 500 cm3 of diethyl ether and with 3 times 500 cm3 of ethyl acetate. The aqueous phase is then acidified with citric acid solution to pH 3 (the formation of a precipitate is observed) and extracted with twice 1000 cm3 of diethyl ether. The organic phase is dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa), and the yellow solid obtained is taken up in 300 cm3 of water and stirred for 2 hours at a temperature in the region of 20° C. The mixture is then filtered and the solid is washed with twice 50 cm3 of water, dried under a ventilated hood and then dried under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. 51.3 g of 3,5-dibromo-1H-pyrazole-4-carboxaldehyde are thus obtained in the form of a yellow powder melting at 173° C.
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[C:9]([O:13][C:14]([NH:16][C@@H:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:19][C@H:18]1[OH:33])=[O:15])([CH3:12])([CH3:11])[CH3:10].N1C=CN=C1>CN(C=O)C>[C:9]([O:13][C:14]([NH:16][C@@H:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:19][C@H:18]1[O:33][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7])=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)OCc2ccccc2)C[C@H]1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)OCc2ccccc2)C[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-butyldimethylchlorosilane (6.51 g, 43.2 mmol) was added to a solution of (+/−)(3R,4R)-benzyl 4-((tert-butoxycarbonyl)amino)-3-hydroxypiperidine-1-carboxylate (prepared according to a published literature procedure: Fink, Brian, et al., WO 2005/066176, 10.1 g, 28.8 mmol) and imidazole (3.92 g, 57.6 mmol) in DMF (60 mL). The mixture was stirred at room temperature overnight. Ice water was added and the reaction mixture was extracted with ether twice, the combined extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (330 g column, eluting with 5-20% ethyl acetate/dichloromethane) to give (+/−)-(3R,4R)-benzyl 4-((tert-butoxycarbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)piperidine-1-carboxylate (13.3 g,) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])=[CH:19][CH:18]=2)=[C:12]([C:14]#[N:15])[N:13]=1.C(=O)(O)[O-:32].[Na+].[OH-].[Na+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)=[O:24])=[CH:21][CH:22]=2)=[C:12]([C:14]([NH2:15])=[O:32])[N:13]=1
Reactant: N#Cc1nc(-c2c(F)cccc2F)oc1Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1Nc1ccc(C(=O)N2CCOCC2)cc1
Yield: 77 %

Procedure:
A solution of 2-(2,6-difluorophenyl)-5-(4-(morpholine-4-carbonyl)phenylamino)oxazole-4-carbonitrile (0.009 g, 0.022 mmol) in concentrated sulfuric acid (0.5 mL) was stirred at room temperature for 1.5 hours. The solution was neutralised by pouring into saturated sodium bicarbonate solution. The aqueous phase was then basified to pH14 using 5M NaOH and extracted with EtOAc. The combined organic phase was dried over MgSO4 and the solvent removed in vacuo to afford 2-(2,6-difluorophenyl)-5-(4-(morpholine-4-carbonyl)phenylamino)oxazole-4-carboxamide (0.007 g, 0.017 mmol, 77%) as a yellow solid. 1H NMR (DMSO) δ 3.51 (4H, m), 3.58 (4H, m), 7.32-7.47 (8H, m), 7.64 (1H, m), 9.55 (1H, s). LCMS (2) Rt: 2.14 min; m/z (ES+) 429.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]([CH3:13])([CH3:12])[CH:10]=O)=[CH:4][CH:3]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH:32]1[CH2:35][CH2:34][CH2:33]1>ClCCl.C([O-])(O)=O.[Na+]>[N:32]1([CH2:10][C:9]([CH3:13])([CH3:12])[O:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][CH:6]=2)[CH2:35][CH2:34][CH2:33]1
Reactant: CC(C)(C=O)Oc1ccc(Cl)nc1
Reactant: C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(CN1CCC1)Oc1ccc(Cl)nc1
Temperature: 0 °C

Procedure:
In a 100 pressure flask 2-(6-chloropyridin-3-yloxy)-2-methylpropanal (10 g, 50.1 mmol, Eq: 1.00), acetic acid (5.7 mL, 100 mmol) and sodium triacetoxyborohydride (22.3 g, 105 mmol, Eq: 2.1) were dissolved in dichloromethane (58 mL) and cooled to 0° C. To this solution was added azetidine (11.8 mL, 175 mmol, 3.5 equiv) via dropwise addition. The reaction was heated overnight at 55° C., then cooled to ambient temperature. The reaction mixture was diluted with 120 ml saturated NaHCO3 and 80 ml dichloromethane. Mixture was shaken and the dichloromethane layer collected. The organic layer was washed again with 100 ml of 5% NaHCO3 (aq) solution and with an equal volume of 50% diluted brine. The aqueous phase was back-extracted 2×70 ml dichlormethane. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by Analogix MPLC (SF25-60 gram column) eluted with 100% DCM to 5% MeOH/DCM gradient to afford a 70:30 mixture of the desired product: 2-(6-chloro-pyridin-3-yloxy)-2-methyl-propan-1-ol (7.5 g) as a pale yellow oil. Used as is in the next step.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[S:8](=[O:15])(=[O:14])[CH2:9][CH2:10][S:11](=[O:13])(=[O:12])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:16]([OH:18])=O.S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:1][C:2]1[C:7]2[S:8](=[O:15])(=[O:14])[CH2:9][CH2:10][S:11](=[O:13])(=[O:12])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:16]([Cl:21])=[O:18]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(C(=O)O)ccc2c1S(=O)(=O)CCS2(=O)=O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Cl)ccc2c1S(=O)(=O)CCS2(=O)=O
Reaction time: 4 h

Procedure:
10.0 g (0.0345 mol) of 8-methyl-2,3-dihydro-1,1,4,4-tetraoxobenz-[1,4]dithiin-7-carboxylic acid were dissolved in 100 ml of toluene, and two drops of dimethylformamide and then 4.5 g (0.038 mol) of thionyl chloride were added. After four hours of stirring under reflux, the mixture was concentrated. The colorless oil that remained (yield 10.6 g) could be directly employed further.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[N:5][CH:4]=1.[CH:15]1([C:18](Cl)=[O:19])[CH2:17][CH2:16]1.C(Cl)Cl>C(=O)([O-])[O-].[Na+].[Na+].O>[Cl:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:10][CH2:11][N:12]([C:18]([CH:15]3[CH2:17][CH2:16]3)=[O:19])[CH2:13][CH2:14]2)[CH:6]=[N:5][CH:4]=1
Reactant: O=C(Cl)C1CC1
Reactant: Clc1cncc(N2CCNCC2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(C1CC1)N1CCN(c2cncc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 93.7 %

Procedure:
To a stirred suspension of 4.70 g (20.0 mmol) of 6-chloro-2-(1-piperazinyl)-pyrazine hydrochloride in 75 ml saturated aqueous sodium carbonate cooled in an ice bath is added 3 ml (33 mmol) of cyclopropanecarboxylic acid chloride. The mixture is stirred 45 minutes at ice bath temperature and then treated with 5 ml methylene chloride and warmed to room temperature during 30 minutes. Additional acid chloride (3 ml, 33 mmol) is added and stirring is continued 30 minutes longer. The mixture is diluted with water and extracted with chloroform to give 5 g crude 6-chloro-2-(4-cyclopropanecarbonyl-1-piperazinyl)-pyrazine which crystallizes, mp 69°-71° C. (100%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:34][N:35]1[CH:39]=[N:38][C:37]([C:40]([OH:42])=O)=[N:36]1.[NH:43]1[C:51]2[C:46](=[C:47]([C:52]3[CH:53]=[C:54]([NH2:61])[C:55]4[CH:56]=[N:57][NH:58][C:59]=4[CH:60]=3)[CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44]1>CN(C=O)C>[NH:43]1[C:51]2[C:46](=[C:47]([C:52]3[CH:60]=[C:59]4[C:55]([CH:56]=[N:57][NH:58]4)=[C:54]([NH:61][C:40]([C:37]4[N:38]=[CH:39][N:35]([CH3:34])[N:36]=4)=[O:42])[CH:53]=3)[CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44]1
Reactant: Cn1cnc(C(=O)O)n1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cnc(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)n1
Reaction time: 0.5 h
Yield: 51.4 %

Procedure:
HATU (248 mg) and DIPEA (0.211 ml) were added to a flask containing 1-methyl-1H-1,2,4-triazole-3-carboxylic acid (51 mg) in DMF (1 ml). The reaction was stirred for 30 min under nitrogen. 6-(1H-Indol-4-yl)-1H-indazol-4-amine (50 mg) was added and the mixture was stirred for 3 h at RT under nitrogen. The reaction mixture was applied to an aminopropyl SPE cartridge (5 g) and left for 3 h. The column was washed with 10% methanol in DCM. The appropriate fractions were combined and the solvent was evaporated. The residue was dissolved in methanol:DMSO (1 ml, 1:1) and purified by mass directed preparative HPLC (Method A) to give title compound (37 mg).
Reaction SMILES: [Li+].[Cl-].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].[CH2:14]([O:21][C:22](=[O:35])[NH:23][CH:24]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:25]CC=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C.C(OCC)C.[NH4+].[Cl-]>[CH3:3][O:4][C:5](=[O:6])[CH2:7][CH2:25][CH:24]([NH:23][C:22]([O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: O=CCCC(NC(=O)OCc1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CC#N
Solvent: CCOCC
Product: COC(=O)CCC(NC(=O)OCc1ccccc1)c1ccccc1
Reaction time: 0.08 h
Yield: 81.6 %

Procedure:
To a stirring room temperature suspension of LiCl (0.84 g, 19.8 mmol) in dry acetonitrile (50 mL) was added trimethyl phosphonoacetate (4 mL, 24.75 mmol). The resulting mixture was stirred for 5 minutes, then TEA (2.76 mL, 19.8 mmol) was added. The reaction mixture was stirred for 10 minutes, and then a solution of (4-oxo-1-phenyl-butyl)-carbamic acid benzyl ester (16.5 mmol) in acetonitrile (15 mL) was added. The reaction mixture was stirred at room temperature for 18 hours, then diluted with diethyl ether and saturated aqueous NH4Cl. The organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to an oil, which was chromatographed (5%-40% EtOAc in hexanes) to give 4.41 g (79%) of 4-benzyloxycarbonylamino-4-phenyl-butyric acid methyl ester as a colorless oil.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:14][C:15]([CH3:20])([CH3:19])[CH2:16][CH:17]=O.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:17][CH2:16][C:15]([CH3:20])([CH3:19])[CH3:14])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)CC=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)CCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a solution of 1-boc-piperazine (8.19 g, 43.9 mmol) in methanol/acetic acid (99:1, v/v, 100 ml) was added 3,3-dimethylbutyraldehyde (4.0 g, 40.0 mmol) and the resulting mixture was stirred at room temperature for 1 h. Sodium cyanoborohydride (3.27 g, 51.9 mmol) was added, and the resulting mixture was stirred at room temperature for 18 h then concentrated in vacuo. The residue was dissolved in EtOAc and the resulting solution was washed with saturated NaHCO3, water and brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 5% methanol:95% EtOAc) to yield the title compound (9.1 g, 84%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH2:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:30]>O1CCCC1.CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:26])[F:24])[CH:18]=2)[CH2:15][O:16][CH3:30])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCN(C(CO)c2cccc(C(F)(F)F)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCC(c1cccc(C(F)(F)F)c1)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
A mixture of 4-[2-Hydroxy-1-(3-trifluoromethyl-phenyl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (200 mg, 0.53 mmol) in tetrahydrofuran (5 mL) and N,N-dimethylformamide (5 mL) at 0° C. was added sodium hydride (60% in mineral oil, 70 mg, 1.75 mmol) followed by iodomethane (230 mg, 1.62 mmole). The mixture was stirred at 0° C. for three hours. The reaction was quenched with saturated aqueous ammonium chloride solution and partitioned between ethyl acetate and water. The organic layer was dried with magnesium sulfate. Filtration, concentration gave a crude oil which was loaded onto a column of silica gel. Elution with 50% ethyl acetate/hexanes gave 4-[2-Methoxy-1-(3-trifluoromethyl-phenyl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (190 mg, 92% yield) as a colorless oil. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][C@@H:12]([CH2:15][CH3:16])[CH2:13]O.S(=O)(=O)(O)O.O>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:11][CH:12]([CH3:13])[CH2:15][CH3:16])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CC[C@H](C)CO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(C)COC(=O)c1ccc(O)cc1
Yield: 82.9 %

Procedure:
4.0 g of p-hydroxybenzoic acid and 12.5 g of (S)-(-)-2-methylbutanol were refluxed for 6 hours in toluene in the presence of sulfuric acid, while the generated water was removed out. Subsequently, the reaction solution was washed with water to remove sulfuric acid out. After the resulting solution was dried and concentrated, the concentrate was purified by column chromatography to obtain 5.0 g of the objective ester compound (liquid state at room temperature, [α]D23 =+4.9° (CHCl3)). (Yield: 83%)
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[NH:5][C:6]=1I.CN(C)C=O.S([O-])([O-])=O.[Na+].[Na+]>O>[I:1][C:2]1[NH:3][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:5][CH:6]=1
Reactant: Ic1nc(-c2ccccn2)[nH]c1I
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Ic1cnc(-c2ccccn2)[nH]1
Temperature: 120 °C
Reaction time: 24 h
Yield: 88.2 %

Procedure:
To a solution of 2-(4,5-diiodo-1H-imidazol-2-yl)pyridine (18.6 g) in a mixed solvent of N,N-dimethylformamide (200 mL) and water (100 ml) was added sodium sulfite (35.4 g), and the mixture was stirred at 120° C. for 24 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:99-20:80, volume ratio) to give the title compound (11.2 g, yield 88%) as colorless crystals. melting point 175-179° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:5]2[N:6]([C:8]([CH3:11])=[N:9][N:10]=2)[N:7]=1.[C:19](O)(=O)C.C=O.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:12][CH:13]2[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]2)[C:5]2[N:6]([C:8]([CH3:11])=[N:9][N:10]=2)[N:7]=1
Reactant: Cc1nnc2c(NC3CCNCC3)cc(Cl)nn12
Reactant: CC(=O)O
Agent: C=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1nnc2c(NC3CCN(C)CC3)cc(Cl)nn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(6-Chloro-3-methyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl)-piperidin-4-yl-amine (0.26 g; 0.97 mmol) was dissolved in 5.0 ml THF. Acetic acid (0.11 ml; 1.94 mmol), formaldehyde 37% in water (0.29 ml; 3.89 mmol) and STAB (0.27 g; 1.27 mmol) were added and stirred at ambient temperature for 1 hour. The crude material was purified by using reversed phase chromatography under basic conditions.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:31][C:32]1([CH3:39])[C:36]([CH3:38])([CH3:37])[O:35][BH:34][O:33]1>C(#N)C>[CH3:31][C:32]1([CH3:39])[C:36]([CH3:38])([CH3:37])[O:35][B:34]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)=[CH:4][CH:3]=2)[O:33]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCc2ccc(Br)cc2)CC1
Reactant: CC1(C)OBOC1(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(CCCc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of tert-butyl 4-(3-(4-bromophenyl)propyl)piperazine-1-carboxylate (2.4 g, 6.26 mmol) in acetonitrile (12 ml) was added triethylamine (2.62 ml, 18.78 mmol) and Pd-118 (0.122 g, 0.19 mmol). Reaction mixture was stirred at RT under nitrogen for 10 min. 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (1.363 ml, 9.39 mmol) added and reaction mixture heated to 80° C. for 1 h. The reaction mixture was evaporated to dryness and redissolved in EtOAc and washed with water and saturated brine. The organic was dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography using Isco Companion, 100 g silica column, elution gradient 40 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford sub-title compound as a brown oil. Yield: 0.9 g
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:8][NH2:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.OO.[O-]Cl.[Na+]>O.CO>[CH2:2]1[C:3]2([CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:8][N:9]=[N:1]1
Reactant: NCC1(CN)CCCC1
Agent: OO
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: CO
Product: C1CCC2(C1)CN=NC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
C-(1-Aminomethyl-cyclopentyl)-methylamine (4.87 g) was taken up in a mixture of H2O (40 mL) and MeOH (10 mL), and cooled in an ice bath. Simultaneously, H2O2 (23.9 mL of a 30% solution, 6 equiv.) and NaClO (54.3 mL of a 10% solution, 2.4 equiv.) were added dropwise, the ice bath was removed, and the mixture was stirred for 2 h. at room temperature. Extraction with DCM, drying over Na2SO4 and evaporation under reduced pressure yielded 3.74 g of a clear, light-yellow liquid containing 90% of the anticipated product and 10% of the diamine starting material. This material was used in subsequent steps without further purification. 1H NMR (400 MHz, CDCl3) δ 1.48-1.57 (m, 4H), 1.62-1.69 (m, 4H), 4.26 (s, 4H).
Reaction SMILES: O[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:22]>C(Cl)Cl>[Cl:22][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1
Reactant: Oc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: Clc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 100 °C

Procedure:
A stirred solution of 2-Hydroxy-5,6-diphenylpyrazine (430 mg, 1.7 mmol) in 5.2 mL POCl3 in a capped reaction vial was heated to 100° C. for 4 hours. The orange solution was cooled to room temperature and stirred rapidly in a mixture of CH2Cl2 (100 mL) and ice cold 10% Na2CO3 (100 mL) for 15 minutes. The organic layer was isolated and washed 2×100 mL with 10% Na2CO3. The organics were isolated, dried (MgSO4), filtered and concentrated to the chloropyrazine, which existed as white solid (450 mg, quantitative). 1H-NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 7.45-7.39 (m, 4H), 7.36-7.24 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[CH:6]=[N:5]2.[C:20]([N:22]([CH2:28][CH3:29])[C:23](=[O:27])[CH:24](Br)[CH3:25])#[N:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:20]([N:22]([CH2:28][CH3:29])[C:23](=[O:27])[CH:24]([O:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:7]2[CH:6]=[N:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=3)[N:8]=2)=[CH:14][CH:15]=1)[CH3:25])#[N:21]
Reactant: CCN(C#N)C(=O)C(C)Br
Reactant: Oc1ccc(Oc2cnc3cc(F)ccc3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(C#N)C(=O)C(C)Oc1ccc(Oc2cnc3cc(F)ccc3n2)cc1
Yield: 47.9 %

Procedure:
10 g (0.039 mole) of 4-(6-fluoroquinoxalin-2-yloxy)phenol, 9.6 g (0.047 mole) of 2-bromopropionic acid N-cyano-N-ethylamide and 8.1 g (0.058 mole) of potassium carbonate are stirred for 14 hours at room temperature in 100 ml of acetonitrile. The precipitated salts are removed by filtration and the filtrate is concentrated by evaporation. The residue is chromatographed through silica gel eluted with ethyl acetate/hexane (1:3), affording 7.1 g (48% of theory) of 2-[4-(6-fluoroquinoxalin-2-yloxy)phenoxy]propionic acid N-cyano-N-ethylamide with a melting point of 108°-111° C.
Reaction SMILES: O[Li].O.[Br:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:15][N:16]2[C:22](=[O:23])[C@@H:21]([NH:24][C:25](=[O:37])[C@@H:26]([N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH3:29])[CH3:27])[CH2:20][O:19][C:18]3[C:38]([C:42]([O:44]C)=[O:43])=[CH:39][CH:40]=[CH:41][C:17]2=3)=[CH:7][CH:6]=1>CO>[Br:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:15][N:16]2[C:22](=[O:23])[C@@H:21]([NH:24][C:25](=[O:37])[C@@H:26]([N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH3:29])[CH3:27])[CH2:20][O:19][C:18]3[C:38]([C:42]([OH:44])=[O:43])=[CH:39][CH:40]=[CH:41][C:17]2=3)=[CH:7][CH:6]=1
Reactant: COC(=O)c1cccc2c1OC[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N2Cc1ccc(Br)c2ccccc12
Agent: [Li]O
Solvent: O
Solvent: CO
Product: C[C@@H](C(=O)N[C@H]1COc2c(C(=O)O)cccc2N(Cc2ccc(Br)c3ccccc23)C1=O)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 77.9 %

Procedure:
A 0.1 M solution of LiOH.H2O (8.87 mL, 887 μmol, Eq: 1.00) was added to a solution of (S)-methyl 5-((4-bromonaphthalen-1-yl)methyl)-3-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-9-carboxylate (568 mg, 887 μmol, Eq: 1.00) in MeOH (10 mL) at 0° C. The mixture was stirred at RT for 20 min. then heated to 40° C. After 6.5 h the MeOH was removed in vacuo and the aqueous mixture diluted with sat. NaHCO3 and extracted with Et2O. The aqueous mixture was cooled 0° C., acidified to pH 3 with 3 N HCl and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated to afford the title compound (433 mg, 78%) as a white foam which was used without purification.