Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[S:7][CH:8]=1)([OH:3])=O.Cl.[CH2:23]([NH:25][CH:26]([CH3:35])[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28])[CH3:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH2:23]([N:25]([CH:26]([CH3:35])[C:27](=[O:28])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:1]([C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[S:7][CH:8]=1)=[O:3])[CH3:24]
Reactant: CCNC(C)C(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C(=O)O)cs2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(C(=O)c1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1)C(C)C(=O)c1ccccc1

Procedure:
tert-Butyl 4-(4-carboxythiazol-2-yl)piperidine-1-carboxylate (6.5 mmol; 2.03 g) is dissolved in 40 ml of anhydrous dimethylformamide and placed under an inert atmosphere, and 2-(ethylamino)propiophenone hydrochloride (1 eq.; 6.5 mmol; 1.39 g), HBTU (1 eq.; 6.5 mmol; 2.47 g) and N-ethyldiisopropylamine (3.5 eq.; 22.75 mmol; 3.97 ml) are then added.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:15])[CH2:4][N:5]([CH2:10][CH:11]([OH:14])[CH2:12]Cl)[CH2:6][C:7]([OH:9])=[O:8].[Na].[OH-].[Na+]>O>[O:14]1[CH2:12][CH:11]1[CH2:10][N:5]([CH2:4][CH:3]1[O:15][CH2:2]1)[CH2:6][C:7]([OH:9])=[O:8]
Reactant: O=C(O)CN(CC(O)CCl)CC(O)CCl
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: O=C(O)CN(CC1CO1)CC1CO1
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
A reactor was charged with 20 g (0.07 mole) of sodium N,N-bis(3-chloro-2-hydroxypropyl)glycine obtained in the same manner as in Referential Example 1 and 100 g of water, and the contents were kept at 50° C., to which 35 ml of a 4N aqueous solution of sodium hydroxide were added. After the mixture was stirred for 30 minutes, the solvent was distilled off under reduced pressure, and 100 ml of ethanol were added to the residue to separate insoluble matter by filtration. Thereafter, ethanol was distilled off under reduced pressure, thereby obtaining 11 g (isolation yield: 84%) of N,N-bis(2,3-epoxypropyl)glycine.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].[N:16]1([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>CC#N>[Si:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:19]1[CH2:18][CH2:17][N:16]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:21][CH2:20]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCBr
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OCCCCCCN1CCN(C(=O)OCc2ccccc2)CC1
Yield: 69.8 %

Procedure:
Intermediate 19 (2.6 g, 8.8 mmol) was added to a stirring solution of benzyl piperazine-1-carboxylate (1.1 mL, 5.87 mmol) in CH3CN (80 mL). The reaction mixture was refluxed over night, cooled, and quenched with satd. NaHCO3 (100 mL). The aqueous layer was extracted with EtOAc (3×50 mL) and the combined organic layers were washed with brine, dried over Na2SO4, concentrated to give the crude (3.8 g) as opaque oil. The chromatography (1:3, hexanes/EtOAc) afforded the title compound (1.78 g, 70%) as clear oil. ES/MS calcd. for C24H43N2O3Si+ 435.3. Found m/z=435.2 (M+H)+.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:15][C:16]1[C:21]2[C:22](=[O:26])[NH:23][N:24]=[CH:25][C:20]=2[CH:19]=[N:18][CH:17]=1.[N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[CH2:37][CH2:38]O.C(Cl)Cl>C1COCC1.O>[Cl:15][C:16]1[C:21]2[C:22](=[O:26])[N:23]([CH2:38][CH2:37][C:28]3[CH:29]=[CH:30][C:31]4[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:27]=3)[N:24]=[CH:25][C:20]=2[CH:19]=[N:18][CH:17]=1
Reactant: O=c1[nH]ncc2cncc(Cl)c12
Reactant: OCCc1ccc2ccccc2n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=c1c2c(Cl)cncc2cnn1CCc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
To 69.3 mg (0.264 mmol) in THF was added diisopropylazodicarboxylate (94 mg, 0.463 mmol) in THF under ice-cooling and under nitrogen. Then, the resulting solution was stirred for 30 min at room temperature to give a suspension. 8-Chloropyrido[4,3-d]pyridazin-1(2H)-one (24 mg, 0.132 mmol) in THF and then 2-(quinolin-2-yl)ethanol (22.89 mg, 0.132 mmol) in THF were added and the reaction mixture was stirred overnight at room temperature. The total amount of THF was 60 mL. Then, the reaction mixture was mixed with DCM and water. The organic phase was washed with 1N HCl and the organic phase was discharged. The aqueous phase was basified by 1N NaOH and extracted with DCM. The organic phase was dried and concentrated to give 34 mg (76%) of the title compound as bright beige solid. LC-MS: m/e 337.1 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[S:13][C:12]2[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7](=S)[C:6]=2[N:5]=1)([CH3:3])[CH3:2].O(C)S(C(F)(F)F)(=O)=O.[CH3:28][O:29][CH2:30][CH2:31][CH2:32][C@H:33]1[CH2:38][NH:37][CH2:36][CH2:35][NH:34]1.N1C=CC=CC=1>ClCCl>[CH3:28][O:29][CH2:30][CH2:31][CH2:32][C@@H:33]1[NH:34][CH2:35][CH2:36][N:37]([C:7]2[C:6]3[N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[S:13][C:12]=3[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=2)[CH2:38]1
Reactant: CC(C)c1nc2c(s1)Nc1ccccc1NC2=S
Reactant: COCCC[C@H]1CNCCN1
Agent: COS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C(C)C)nc32)CCN1

Procedure:
Combine 2-isopropyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo[f]azulene-10-thione (0.5 g, 1.816 mmol), methyl triflate (0.306 mL, 2.723 mmol) in dichloromethane (4 mL) and stir at ambient temperature for 2 hours. Evaporate the mixture uner reduced pressure and then combine the residue with (S)-2-(3-methoxy-propyl)-piperazine (0.287 g, 1.816 mmol) and pyridine (4 mL) and reflux for 8 hours. Concentrate the reaction mixture under reduced pressure and dilute the residue with ethyl acetata. Wash the organic with brine twice, dry over sodium sulfate, filter and concentrate under reduced pressure to give a residue. Purify the residue by flash chromatography, eluting with 2M ammonia in methanol:dichloromethane (5:95) to give the title compound: mass spectrum (m/e):400.03 (M+1).
Reaction SMILES: [CH:1]1([CH2:4][C:5]([F:36])([F:35])[CH2:6][C@H:7]([NH:22][CH2:23][C:24]([F:34])([F:33])[O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[C:8]([NH:10][C@@H:11]([CH2:20][CH3:21])[CH:12]([OH:19])[C:13]([NH:15][CH:16]2[CH2:18][CH2:17]2)=[O:14])=[O:9])[CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CN1CCCC1>[CH:1]1([CH2:4][C:5]([F:36])([F:35])[CH2:6][C@H:7]([NH:22][CH2:23][C:24]([F:33])([F:34])[O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[C:8]([NH:10][C@@H:11]([CH2:20][CH3:21])[C:12](=[O:19])[C:13]([NH:15][CH:16]2[CH2:17][CH2:18]2)=[O:14])=[O:9])[CH2:3][CH2:2]1
Reactant: CC[C@H](NC(=O)[C@H](CC(F)(F)CC1CC1)NCC(F)(F)Oc1ccc(F)cc1)C(O)C(=O)NC1CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CN1CCCC1
Agent: O=C([O-])O
Product: CC[C@H](NC(=O)[C@H](CC(F)(F)CC1CC1)NCC(F)(F)Oc1ccc(F)cc1)C(=O)C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
To a solution of (2S)-5-cyclopropyl-N-((3S)-1-(cyclopropylamino)-2-hydroxy-1-oxopentan-3-yl)-2-(2,2-difluoro-2-(4-fluorophenoxy)ethylamino)-4,4-difluoropentanamide (190 mg, 0.36 mmol) in N-methylpyrrolidine (4 ml) was added Dess-Martin periodinane reagent (216 mg, 0.51 mmol, 1.4 eq). The mixture was stirred for 4 hours at room temperature, then added to saturated aqueous sodium bicarbonate (50 ml) containing sodium thiosulfate (1.5 g). The mixture was stirred for 1 hour, filtered, the solid material washed with water, then dried in a vacuum oven at 40° C. using phosphorus pentoxide as a drying agent, yielding (S)-5-cyclopropyl-N-((S)-1-(cyclopropylamino)-1,2-dioxopentan-3-yl)-2-(2,2-difluoro-2-(4-fluorophenoxy)ethylamino)-4,4-difluoropentanamide 144 mg (76%).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.[OH:6][C@@H:7]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[S:22][C:21]3[C:16](=[N:17][CH:18]=[CH:19][C:20]=3[Cl:23])[CH:15]=2)=[O:13])[CH2:8]1>>[Cl:23][C:20]1[CH:19]=[CH:18][N:17]=[C:16]2[CH:15]=[C:14]([C:12]([N:9]3[CH2:10][CH2:11][C@@H:7]([O:6][CH2:2][CH:3]4[CH2:5][CH2:4]4)[CH2:8]3)=[O:13])[S:22][C:21]=12
Reactant: BrCC1CC1
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CC[C@@H](O)C1
Product: O=C(c1cc2nccc(Cl)c2s1)N1CC[C@@H](OCC2CC2)C1

Procedure:
The title compound was prepared from bromomethyl-cyclopropane and (3R)-(3-hydroxy-pyrrolidin-1-yl)-[7-chloro-thieno[3,2-b]pyridin-2-yl]-methanone by a procedure analogous to Example 67B. MS: 337.2/339.2 (MH+); HPLC Rf: 5.232 min.; HPLC purity 85%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[C:9]([CH3:16])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.O1CCCC1.[C].[Pd]>[C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([CH3:16])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(C(=O)OC(C)(C)C)ccc1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 106.2 %

Procedure:
The compound (55.6 g, 234 mmol) obtained in step A was dissolved in an ethanol (200 ml)-tetrahydrofuran (100 ml) mixed solvent. Then, 10% palladium carbon (containing water) (10 g) suspended in ethanol (20 ml) was added. Under a hydrogen atmosphere and at room temperature, the reaction mixture was stirred for 5 hr, and filtered off through celite. The obtained solution was concentrated under reduced pressure to give the title compound (51.5 g) as a bistered oil.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([O:15]CC=C)=[CH:7][C:6]=1[C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:3])[CH3:2].C(O[C:27]1[C:32](C(C)(C)C)=CC(O)=C(OCC=C)[C:28]=1C(C)(C)C)(=O)C>CN(C)C1C=CC=CC=1>[C:1]([O:4][C:5]1[C:10]([C:11]([CH3:13])([CH3:12])[CH3:14])=[CH:9][C:8]([OH:15])=[C:7]([CH2:32][CH:27]=[CH2:28])[C:6]=1[C:19]([CH3:22])([CH3:20])[CH3:21])(=[O:3])[CH3:2]
Reactant: C=CCOc1cc(C(C)(C)C)c(OC(C)=O)c(C(C)(C)C)c1
Reactant: C=CCOc1c(O)cc(C(C)(C)C)c(OC(C)=O)c1C(C)(C)C
Solvent: CN(C)c1ccccc1
Product: C=CCc1c(O)cc(C(C)(C)C)c(OC(C)=O)c1C(C)(C)C
Temperature: 25 °C
Yield: 165 %

Procedure:
Synthesis of 4-Acetoxy-3,5-Di-tert-Butyl-2-(2-Propenyloxy)phenol 4-Acetoxy-3,5-di-tert-butyl-1-(2-propenyloxy)benzene (11.0 g) was dissolved in N,N-dimethylaniline (50 ml) and the solution was refluxed for 18 h under a nitrogen atmosphere. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and purified by silica gel chromatography (15% ethyl acetate in n-hexane) to afford 4-acetoxy-3,5-di-tert-butyl-2-(2propenyl)phenol [8.84 g (yield, 77%)] as a white solid.
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([C:13]2[O:14][C:15]3[C:35]([O:36]CC4C=CC=CC=4)=[C:34]([O:44][CH3:45])[CH:33]=[CH:32][C:16]=3[C:17]=2[C:18]([C:20]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=2)=[O:19])[CH:10]=[N:9]1)C1C=CC=CC=1>[Pd].Cl.C(OCC)(=O)C.CO>[OH:36][C:35]1[C:15]2[O:14][C:13]([C:11]3[CH:10]=[N:9][NH:8][CH:12]=3)=[C:17]([C:18]([C:20]3[CH:21]=[C:22]([O:30][CH3:31])[C:23]([O:28][CH3:29])=[C:24]([O:26][CH3:27])[CH:25]=3)=[O:19])[C:16]=2[CH:32]=[CH:33][C:34]=1[O:44][CH3:45]
Reactant: COc1cc(C(=O)c2c(-c3cnn(Cc4ccccc4)c3)oc3c(OCc4ccccc4)c(OC)ccc23)cc(OC)c1OC
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(C(=O)c2c(-c3cn[nH]c3)oc3c(O)c(OC)ccc23)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of crude [2-(1-benzyl-1H-pyrazol-4-yl)-7-benzyloxy-6-methoxy-benzofuran-3-yl]-(3,4,5-trimethoxyphenyl)-methanone (29 mg), 10% palladium on carbon (20 mg) and 6M HCl(aq) (2 drops) in ethyl acetate (2 mL) and methanol (1 mL) was stirred at room temperature overnight. After this time the reaction mixture was filtered through celite and the solvent removed under vacuum. The crude residue was purified by preparative thin layer chromatography to afford the product as a pale yellow resin that was solidified by freeze-drying with t-butanol (5 mg, 2% over two steps).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@@:7]1([CH2:17][CH:18]=O)[CH2:16][C:11]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][CH2:27][NH2:28])[CH:21]=1.[BH4-].[Na+]>CO.C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@@:7]1([CH2:17][CH2:18][NH:28][CH2:27][CH2:26][C:22]2[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=2)[CH2:16][C:11]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1
Reactant: NCCc1cccnc1
Reactant: O=CC[C@@]1(c2ccccn2)CCOC2(CCCC2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: c1ccc([C@]2(CCNCCc3cccnc3)CCOC3(CCCC3)C2)nc1
Reaction time: 8 h

Procedure:
To a solution of 2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]acetaldehyde (50 mg, 0.19 mmole), 5 mL DCM and NA2SO4 (134 mg, 0.95 mmole) was added 2-(pyridin-3-yl)ethan-1-amine (31 mg, 0.25 mmole) and the reaction was stirred overnight. NaBH4 (9.5 mg, 0.25 mmole) added, stir 10 minutes, 2 drops MeOH added, stir 1 h, quenched with water, organics separated off and evaporated. The residue was passed through a Gilson reverse phase HPLC to give {2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl}[2-(pyridin-3-yl)ethyl]amine, 65.3 mg (71%). LCMS m/z 367.1 (M+1) observed.
Reaction SMILES: Br[C:2]1[C:3]2[C:28]([CH3:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:27](=[O:35])[NH:26][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[N:9]=2)[N:7]=1.[CH3:36][NH2:37]>C1COCC1>[CH3:34][C:28]1([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:3]2[C:2]([NH:37][CH3:36])=[N:7][C:6]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:17][CH2:18][C:19]([F:24])([F:25])[C:20]([F:23])([F:22])[F:21])[N:9]=3)=[N:5][C:4]=2[NH:26][C:27]1=[O:35]
Reactant: CN
Reactant: CCOC(=O)C1(C)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(Br)c21
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(NC)c21

Procedure:
The intermediate from Step A above (190 mg, 0.337 mmol), methylamine (2M in THF) (0.843 mL, 1.687 mmol) and THF (2 mL) were sealed in a microwave tube and subjected to microwave irradiation at 150° C. for 3 h. The reaction mixture was partitioned between brine and EtOAc. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford a dark solid. The residue was purified by reverse phase preparative HPLC to give the title product, as a solid. 1H NMR (500 MHz, DMSO-d6): δ 11.35 (s, 1H); 8.87 (d, J=8.1 Hz, 1H); 8.64-8.62 (m, 1H); 7.39 (dd, J=8.1, 4.5 Hz, 1H); 6.61 (d, J=4.9 Hz, 1H); 4.88 (t, J=6.8 Hz, 2H); 4.12-4.07 (m, 2H); 3.04-2.90 (m, 5H); 1.61 (s, 3H); 1.09 (t, J=7.1 Hz, 3H). m/z=514.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]([OH:14])=O)[C:8]([OH:11])=[N:9][CH:10]=1)=[O:4].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH2:38]([NH2:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN(C)C=O.O>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:6]=[C:7]([C:12](=[O:14])[NH:45][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:8]([OH:11])=[N:9][CH:10]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)c1cnc(O)c(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(O)c(C(=O)NCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
To a mixture of 2-hydroxy-pyridine-3,5-dicarboxylic acid 5-methyl ester, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC. HCl 0.49 g, 2.6 mmol), 1-hydroxybenzotriazole hydrate (HOBT 0.35 g, 2.6 mmol), in dimethylformamide (10 ml) was added benzylamine 0.27 g (2.6 mmol). The mixture was stirred overnight at room temperature. Water was added (20 ml), and the mixture was filtered. The solid product was slurried in hot ethyl acetate to give 0.17 g (28% yield) of the title compound. MS: m/z (APCI, AP+) 287 [M.]+. CHN Analysis: C15H14N2O4.0.47 H2O; Calcd: C, 61.12; H, 5.11; N, 9.50. Found: C, 61.17; H, 4.81; N, 9.71.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-])=O)=[C:5]([C:18]([OH:20])=[O:19])[CH:4]=1)[CH3:2]>C(O)C.[Pd]>[NH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[NH:8][C:6]1[S:7][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=1[C:18]([OH:20])=[O:19]
Reactant: CCc1cc(C(=O)O)c(Nc2ccccc2[N+](=O)[O-])s1
Agent: [Pd]
Solvent: CCO
Product: CCc1cc(C(=O)O)c(Nc2ccccc2N)s1

Procedure:
5-Ethyl-2-(2-nitroanilino)-thiophene-3-carboxylic acid (8.0 g, 0.027 mol) in ethanol (150 ml) was catalytically reduced over 10% palladium on charcoal (900 mg) at 60 p.s.i. The catalyst was removed by filtration and the solvent removed by distillation in vacuo to give the title compound.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([OH:16])=O)[CH:12]=2)[CH:7]=[N:6]1)[CH2:2][CH2:3][CH3:4].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:51][C@@H:52]([CH2:66][C:67]1[CH:72]=[C:71]([F:73])[CH:70]=[C:69]([F:74])[CH:68]=1)[C@H:53]([OH:65])[CH2:54][NH:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63][CH3:64])[CH:58]=1>C(Cl)Cl.C(N(CC)CC)C>[CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([NH:51][C@@H:52]([CH2:66][C:67]3[CH:68]=[C:69]([F:74])[CH:70]=[C:71]([F:73])[CH:72]=3)[C@H:53]([OH:65])[CH2:54][NH:55][CH2:56][C:57]3[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63][CH3:64])[CH:58]=3)=[O:16])[CH:12]=2)[CH:7]=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCCn1ncc2ccc(C(=O)O)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCn1ncc2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc21
Temperature: 40 °C
Reaction time: 3 h
Yield: 40.8 %

Procedure:
To a mixture of 1-butyl-1H-indazole-6-carboxylic acid (0.2 g) in methylene chloride (20 mL) was added triethylamine (0.182 g), HOBT (126 g), and HATU (0.348 g). The mixture was stirred at 40° C. for 10 minutes at which time (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (0.35 g) was added. The mixture was stirred at 40° C. for 3 h then poured into methylene chloride (50 mL), washed with water then brine, dried over anhydrous magnesium sulfate and concentrated under vacuum. Column chromatography on silica gel (100 mL) using 5% methanol in methylene chloride as eluent to give 0.2 g of the title compound: MS (ESI+) for C31H36F2N4O2 m/z 534.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([OH:22])=O)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[Cl:23][C:24]1[N:25]=[N:26][C:27]([N:30]([CH3:32])[NH2:31])=[CH:28][CH:29]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([C:20]([NH:31][N:30]([C:27]3[N:26]=[N:25][C:24]([Cl:23])=[CH:29][CH:28]=3)[CH3:32])=[O:22])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:18])([F:19])[F:17])=[CH:6][CH:7]=1
Reactant: CN(N)c1ccc(Cl)nn1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: CN(NC(=O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1)c1ccc(Cl)nn1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN 1018782-82-5) and 3-chloro-6-(1-methylhydrazinyl)-pyridazine (CAN 76953-33-8) as starting materials; LC-MS (UV peak area/ESI) 96.8%, 472.0538 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[NH:5][C:6]1[C:11]([C:12]#[N:13])=[CH:10][N:9]=[C:8]2[C:14]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[C:15]=3[S:16][C:7]=12.CO>[Fe].O>[NH2:21][C:17]1[C:15]2[S:16][C:7]3[C:8](=[N:9][CH:10]=[C:11]([C:12]#[N:13])[C:6]=3[NH:5][C:4]3[CH:24]=[CH:25][CH:26]=[C:2]([Br:1])[CH:3]=3)[C:14]=2[CH:20]=[CH:19][CH:18]=1
Reactant: N#Cc1cnc2c(sc3c([N+](=O)[O-])cccc32)c1Nc1cccc(Br)c1
Agent: [Fe]
Solvent: O
Solvent: CO
Product: N#Cc1cnc2c(sc3c(N)cccc32)c1Nc1cccc(Br)c1
Reaction time: 12 h

Procedure:
A mixture of 4-(3-bromoanilino)-6-nitro[1]benzothieno[3,2-b]pyridine-3-carbonitrile (0.213 g, 0.5 mmol), iron powder (0.168 g, 3.0 mmol) ammonium chloride (0.325 g, 6.0 mmol), methanol (90 mL) and water (90 mL) is heated at reflux temperature with vigorous stirring under nitrogen for 12 hours. The final mixture is concentrated, and the residue is extracted with ethyl acetate (5×20 mL). The extract is dried over sodium sulfate, evaporated, and re-dissolved in a small volume of chloroform/methanol/DMSO. Purification by silica gel chromatography, eluting with 20:1 chloroform/methanol, yields 6-amino-4-(3-bromoanilino)[1]benzothieno[3,2-b]pyridine-3-carbonitrile as a brown solid, m.p. 256–258° C.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[C:3]=1[C:16]#[N:17].C(N(CC)C(C)C)(C)C.Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29]>CN(C1C=CN=CC=1)C.ClCCCl>[C:16]([C:3]1[C:4]([C:7]2[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=2)=[N:5][S:6][C:2]=1[NH:1][C:28](=[O:29])[O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)#[N:17]
Reactant: N#Cc1c(-c2ccc([N+](=O)[O-])cc2)nsc1N
Reactant: O=C(Cl)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(-c2ccc([N+](=O)[O-])cc2)nsc1NC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a mixture of 5-amino-3-(4-nitrophenyl)isothiazole-4-carbonitrile (394 mg, 1.60 mmol), N,N-diisopropylethylamine (0.836 mL, 4.8 mmol), and catalytic DMAP in 20 mL 1,2-dichloroethane at rt was added phenyl chloroformate (0.301 mL, 2.40 mmol) drop wise over 1 minute. The reaction mixture was stirred at rt for 22 hours, then added directly to a dry packed silica gel column eluting with CHCl3, then gradient 10% to 50% EtOAc in CHCl3. The title compound was obtained as a beige solid (131 mg, 22%) and used as is for the next step.
Reaction SMILES: NC1SC(C2C(F)=CC=CC=2F)=NC=1C(NC1C=NN(C)C=1N1CCCN(C2CNC2)CC1)=O.[CH3:35][N:36]1[C:40]([N:41]2[CH2:47][CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[C:39]([N+:48]([O-:50])=[O:49])[CH:38]=[N:37]1.[C:51]([O:55][C:56]([NH:58][CH2:59][C:60](O)=[O:61])=[O:57])([CH3:54])([CH3:53])[CH3:52].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:35][N:36]1[C:40]([N:41]2[CH2:47][CH2:46][CH2:45][N:44]([C:60](=[O:61])[CH2:59][NH:58][C:56](=[O:57])[O:55][C:51]([CH3:52])([CH3:53])[CH3:54])[CH2:43][CH2:42]2)=[C:39]([N+:48]([O-:50])=[O:49])[CH:38]=[N:37]1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCCNCC1
Agent: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CCCN(C2CNC2)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc([N+](=O)[O-])c1N1CCCN(C(=O)CNC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In the preparation of 362, 1-(2-methyl-4-nitro-pyrazol-3-yl)-1,4-diazepane (105 mg, 0.47 mmol), 2-(tert-butoxycarbonylamino)acetic acid (106 mg, 0.61 mmol) and PyBOP (396 mg, 0.75 mmol) were dissolved in DCM (6 mL). DIPEA (0.49 ml, 2.80 mmol) was added and the mixture was stirred at room temperature for 18 h. The crude reaction mixture was concentrated and the residue was purified via silica gel column chromatography (0-100% EA/heptane) to gave tert-butyl N-[2-[4-(2-methyl-4-nitro-pyrazol-3-yl)-1,4-diazepan-1-yl]-2-oxo-ethyl]carbamate (qualitative yield).