Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:11]([C:21]23[CH2:30][CH:25]4[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]4)[CH2:22]2)[CH2:28]3)=[CH:10][C:9]=1[C:31]#[CH:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].I[C:34]1[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=1>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[CH2:1]([O:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:11]([C:21]23[CH2:22][CH:23]4[CH2:29][CH:27]([CH2:26][CH:25]([CH2:24]4)[CH2:30]2)[CH2:28]3)=[CH:10][C:9]=1[C:31]#[C:32][C:34]1[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: COC(=O)c1ccc(I)cc1
Reactant: C#Cc1cc(C23CC4CC(CC(C4)C2)C3)c(OCCCCCC)cc1OCCCCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: CCCCCCOc1cc(OCCCCCC)c(C23CC4CC(CC(C4)C2)C3)cc1C#Cc1ccc(C(=O)OC)cc1

Procedure:
1.8 g (4.1 mmol) of 2,4-dihexyloxy-5-(1-adamantyl)phenylacetylene, 1.2 g (4.5 mmol) of methyl 4-iodobenzoate and 15 ml of triethylamine were introduced into a three-necked flask. The reaction mixture was degassed with nitrogen for 15 min, 100 mg of copper iodide and 260 mg (0.37 mmol) of bis(triphenylphosphine)-palladium(II) chloride were added and stirring was carried out at room temperature for twelve hours. The reaction mixture was evaporated to dryness, the residue was taken up in water and ethyl ether and the organic phase was separated by settling, dried over magnesium sulfate and evaporated.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1.[NH:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:26]([O:25][C:23]([N:15]([CH2:2][C:3]1[N:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: BrCc1ccc(-c2ccccc2)nn1
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1ccc(-c2ccccc2)nn1)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
To a solution of 3-bromomethyl-6-phenylpyridazine (120 mg, 0.482 mmol) obtained in Reference Example 2-(a) in N,N-dimethylformamide (1.57 ml) were added di-tert-butyl iminodicarboxylate (127 mg, 0.585 mmol) and potassium carbonate (134 mg, 0.970 mmol), followed by stirring at 50° C. for 2 hours. After completion of the reaction, water was added to the reaction solution, followed by extraction with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=2:1→1:1 (V/V)), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (180 mg) as a slightly yellow solid. (Yield: 97%)
Reaction SMILES: [Cl:1][C:2]([Cl:9])([Cl:8])[CH2:3][O:4][C:5](Cl)=[O:6].[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[O:17])[CH:11]=1.[CH3:18][C:19]1[NH:20][C:21](=[O:25])[CH2:22][S:23][CH:24]=1>C(#N)C>[CH3:18][C:19]1[NH:20][C:21](=[O:25])[CH2:22][S:23][C:24]=1[CH:13]1[CH:14]=[CH:15][N:10]([C:5]([O:4][CH2:3][C:2]([Cl:9])([Cl:8])[Cl:1])=[O:6])[CH:11]=[C:12]1[CH:16]=[O:17]
Reactant: CC1=CSCC(=O)N1
Reactant: O=Cc1cccnc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CC#N
Product: CC1=C(C2C=CN(C(=O)OCC(Cl)(Cl)Cl)C=C2C=O)SCC(=O)N1
Reaction time: 0.5 h
Yield: 44 %

Procedure:
2,2,2-Trichloroethylchloroformate (2.13 ml) was added dropwise to a solution of pyridine-3-aldehyde (1.66 g) in dry acetonitrile (50 ml) under ice-cooling, and the mixture was stirred for 0.5 hour. 5-Methyl-2H-1,4-thiazin-3(4H)-one (1.0 g) was added to the mixture. The reaction mixture was further stirred at ambient temperature for 1 hour. The solvent was removed under reduced pressure. The residue was chromatographed on silica gel (Wakogel C-200) column, using ethyl acetate-n-hexane (=1:1) as an eluant. The eluant was recrystallized from ethanol to give the titled compound (1.4 g, yield 44%) as pale yellow crystals.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]1[C:25]([CH3:26])=[CH:24][C:23]([N+:27]([O-])=O)=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19])C1C=CC=CC=1>CO.O1CCCC1.[Pd]>[NH2:27][C:23]1[CH:24]=[C:25]([CH3:26])[C:16]([C:10]2[CH:11]=[CH:12][C:13]([F:15])=[CH:14][C:9]=2[OH:8])=[C:17]([CH:22]=1)[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(C)c1-c1ccc(F)cc1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(N)cc(C)c1-c1ccc(F)cc1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 64 %

Procedure:
Methyl 2-(2-benzyloxy-4-fluorophenyl)-3-methyl-5-nitrobenzoate (Reference Compound No. 1-4-(4), 10.7 g, 27.0 mmol) was dissolved in a mixture of methanol (50 mL) and tetrahydrofuran (50 mL), then 10% palladium on charcoal (1.00 g) was added thereto, and then the reaction mixture was stirred under hydrogen atmosphere (3 kgf/cm2) at room temperature for 3 days. After the mixture was filtered, the solvent was removed under reduced pressure. Ethyl acetate was added to the obtained residue, and then filtered to give the titled reference compound (4.79 g) as a pale gray solid. (Yield 64%)
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:12]=[C:13]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:14]([CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.C(O)(C)C.C(O)C.[CH3:43][S:44]([OH:47])(=[O:46])=[O:45]>ClCCCl>[CH3:43][S:44]([OH:47])(=[O:46])=[O:45].[Cl:1][C:2]1[C:11]2[N:12]=[C:13]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:14]([CH2:15][CH2:16][N:17]3[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCn2c(-c3ccccc3)nc3c(Cl)nc4ccccc4c32)CC1
Agent: CS(=O)(=O)O
Solvent: CCO
Solvent: ClCCCl
Solvent: CC(C)O
Product: Clc1nc2ccccc2c2c1nc(-c1ccccc1)n2CCN1CCNCC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 1.20 g of tert-butyl 4-[2-(4-chloro-2-phenyl-1H-imidazo-[4,5-c]quinolin-1-yl)ethyl]-1-piperazinecarboxylate in 12 ml of 1,2-dichloroethane, 1.2 ml of methanesulfonic acid was added, and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was added with isopropanol and ethanol, and the precipitated crystals were collected by filtration to give 1.24 g of colorless crystals. Recrystallization from methanol gave colorless crystals having the melting point of from 256 to 270° C. (decomposition).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[C:18]([F:20])[C:17]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[C:16]([C:26]#[CH:27])[CH:15]=2)=[O:11])=[CH:6][CH:5]=[C:4]([C:28]([F:31])([F:30])[F:29])[N:3]=1.[O:32]([CH3:34])[Na]>CO.CCOC(C)=O>[C:26]([C:16]1[CH:15]=[C:14]([CH:19]=[C:18]([F:20])[C:17]=1[NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:13][NH:12][C:10](=[O:11])[CH:9]=[CH:8][C:7]1[C:2]([O:32][CH3:34])=[N:3][C:4]([C:28]([F:31])([F:30])[F:29])=[CH:5][CH:6]=1)#[CH:27]
Reactant: CO[Na]
Reactant: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2Cl)cc(F)c1NS(C)(=O)=O
Solvent: CO
Solvent: CCOC(C)=O
Product: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2OC)cc(F)c1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 20 %

Procedure:
To a suspension of 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl)-acrylamide (50 mg, 0.105 mmol) in CH3OH (1 mL) was added dropwise 30% NaOCH3 in CH3OH (3 eq) at 0° C. The mixture was stirred for 12 hours at room temperature. The reaction was diluted with EtOAc and washed two times with 1N HCl and brine, dried over anhyd. MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give the title compound (10 mg, 20%).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[CH2:6]=[CH:7][CH:8]=[CH2:9]>>[CH2:1]([O:5][CH:8]([CH3:9])[CH:7]=[CH2:6])[CH2:2][CH2:3][CH3:4].[CH2:1]([O:5][CH2:6][CH:7]=[CH:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: C=CC=C
Reactant: CCCCO
Product: C=CC(C)OCCCC
Product: CC=CCOCCCC

Procedure:
A 0.3 1 stirred autoclave was filled with 67.0 g (0.90 mol) of n-butanol and with 11.5 g of Lewatit® SPC 118 in the H+ form, which had been washed beforehand with water and n-butanol, and with 3.5 g of a Lewatit® SPC 118 ion exchanger doped with copper(II) chloride. 47.0 g (0.88 mol) of 1,3-butadiene were then forced into the autoclave. After reaction for 10 hours at 90° C. and under autogeneous pressure, a selectivity of 46.8% for 3-butoxybut-1-ene and a selectivity of 44.3% for 1-butoxybut-2-ene (based on butadiene) were obtained at a conversion of 69.1%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].Br[C@@H:14]([CH3:18])[C:15]([OH:17])=[O:16].O>CN(C=O)C.C(OCCCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@H:14]([CH3:18])[C:15]([OH:17])=[O:16]
Reactant: C[C@H](Br)C(=O)O
Reactant: Fc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](C(=O)O)n1ccc2c(F)cccc21
Temperature: 2.5 °C
Reaction time: 0.33 h
Yield: 27.6 %

Procedure:
To a cooled (0-5° C.) solution of 4-fluoro-indole (44.2 g, 327 mmol) in dry DMF (400 mL) was added sodium hydride (55-65% dispersion in mineral oil, 36 g, 817 mmol) in portions. The resulting suspension was stirred at 0-5° C. for 20 minutes. (2S)-(−)-2-Bromopropionic acid (31.8 mL, 343 mmol) was added dropwise. During the addition, the temperature was kept below 10° C. by cooling in an ice-bath. Upon completion of addition, the mixture was stirred at RT for 2 hours. The mixture was poured into water (1300 mL), and the aqueous solution was washed with heptanes (400 mL) and EtOAc (2×400 mL). The aqueous layer was acidified with concentrated aqueous HCl solution (85 mL, pH<1), and extracted with EtOAc (2×400 mL). The combined organic layers were washed with 1 N aq. HCl solution (2×300 mL) and with a saturated aqueous NaCl solution (300 mL). The solution was dried over sodium sulfate, filtered, and evaporated to dryness to afford a yellow oil (67.6 g, 99%, 82% ee). This oil (67.6 g, 323 mmol) was dissolved in 200 mL n-butyl acetate and (S)-L-(−)-α-methylbenzylamine (41.1 mL, 323 mmol) was added to the warm (50° C.) solution. The mixture was left crystallizing over the weekend. The formed solid was collected by filtration and washed with butyl acetate and heptanes (2×) (68.7 g, 91% ee). This material was recrystallized twice from 500 mL water/15% ethanol (1st recr.: 95% ee, 2nd recr.: 97.5% ee). This material was dissolved in EtOAc (300 mL) and washed with 1 N aqueous HCl (2×200 mL) and saturated aqueous NaCl solution (200 mL), dried over sodium sulfate, filtered, and evaporated to dryness giving (2R)-2-(4-fluoro-indol-1-yl)-propionic acid (18.7 g, 28%) as a greenish oil (purity: 97.5%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[C:20]([CH2:27][NH:28][CH2:29][CH2:30][CH3:31])[CH:19]=2)[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S1C=CC=C1.O=[Si]=O>C1COCC1.[Pt]>[CH2:1]([O:8][C:9](=[O:32])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([CH2:27][NH:28][CH2:29][CH2:30][CH3:31])[CH:19]=2)[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCNCc1cc(Oc2cccc(NC(=O)OCc3ccccc3)c2)ccc1[N+](=O)[O-]
Agent: [Pt]
Agent: O=[Si]=O
Solvent: C1CCOC1
Solvent: c1ccsc1
Product: CCCNCc1cc(Oc2cccc(NC(=O)OCc3ccccc3)c2)ccc1N

Procedure:
A mixture of [3-(4-nitro-3-propylaminomethyl-phenoxy)-phenyl]-carbamic acid benzyl ester (0.033 mol) in THF (200 mL) was hydrogenated with 10% Pt/C (2 g) as a catalyst in the presence of thiophene solution (2 mL). After uptake of H2 gas (3 equiv.), the reaction mixture was filtered through Dicalite, and the filtrate was evaporated. The residue was purified by column chromatography (eluent: 90:10 CH2Cl2:(CH3OH:NH3)). The product fractions were collected, and the solvent was evaporated to yield the title compound as an oil.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2([C:29]([NH:31][OH:32])=[O:30])[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].Cl>O1CCOCC1>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2([C:29]([NH:31][OH:32])=[O:30])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)(=[O:13])=[O:14])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC2(C(=O)NO)CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CC#CCOc1ccc(S(=O)(=O)NC2(C(=O)NO)CCNCC2)cc1

Procedure:
To a solution of tert-butyl 4-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)4-[(hydroxyamino)carbonyl]-1-piperidinecarboxylate (0.114 g) from Example 287, in dioxane (1 mL) was added 4N hydrochloric acid in dioxane (2 mL). After 4 hours the reaction mixture was concentrated in vacuo. Trituration with dichloromethane and diethyl ether gave 4-({[4-(2-butynyloxy)phenyl]sulfonyl)amino)-N-hydroxy-4-piperidinecarboxamide as an off-white powder. Electrospray Mass Spec 368.2 (M+H)+.
Reaction SMILES: C([O:5][N:6]1[CH2:12][CH2:11][CH2:10][N:9]([CH3:13])[C@@H:8]([CH2:14][N:15]([S:33]([CH3:36])(=[O:35])=[O:34])[C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)[C:7]1=[O:37])(C)(C)C.FC(F)(F)C(O)=O.CCCCCC>CCOCC>[OH:5][N:6]1[CH2:12][CH2:11][CH2:10][N:9]([CH3:13])[C@@H:8]([CH2:14][N:15]([S:33]([CH3:36])(=[O:35])=[O:34])[C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)[C:7]1=[O:37]
Reactant: CN1CCCN(OC(C)(C)C)C(=O)[C@@H]1CN(c1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)S(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: CCCCCC
Product: CN1CCCN(O)C(=O)[C@@H]1CN(c1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.6 %

Procedure:
To a suspension of (3S)-1-t-butoxy-3-{N-methanesulfonyl-N-[4-(4-trifluoromethyl-phenoxy)phenyl]amino}methyl-4-methyl-1,4-diazepan-2-one (146 mg, 0.2 mmol) from Step G in Et2O (0.5 mL) at room temperature was added trifluoroacetic acid (1.5 mL) slowly. The mixture was stirred for 1 h at rt. The mixture was poured into Et2O/pure H2O (10 mL/30 mL) and hexane (20 mL) was then added. The organic layer was extracted with pure H2O (30 mL). The aqueous layers were collected and combined. After lyophilization gave 102 mg of the titled compound (85%) as a white trifluoroacetic acid salt. 1H NMR (300 MHz, d6-DMSO) δ 10.05-10.00 (br s, 1H), 7.77 (d, J=9.0 Hz, 2H), 7.56 (d, J=9.0 Hz, 2H), 7.21 (d, J=9.0 Hz, 2H), 7.18 (d, J=9.0 Hz, 2H), 4.5-4.0 (m, 5H), 3.37-3.31 (m, 1H), 3.09-3.06 (m, 4H), 2.51 (br s, 3H), 2.14-1.84 (m, 2H); MS (EI) 510 (M++Na), 488 (M++1, 100).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CN(C=O)C.[C:14]1([CH2:20][CH:21]=[N:22][OH:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OCC)C>O>[C:14]1([CH2:20][C:21]([Cl:1])=[N:22][OH:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ON=CCc1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: ON=C(Cl)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of N-chlorosuccinimide (3.25 g, 24 mmol) in abs. DMF (18 ml) was added to a solution of compound V (2.7 g, 20 mmol) in abs. DMF (12 ml) at a temperature of 30-40° C. within 20 min. Cooling in an ice bath was carried out if necessary. The reaction mixture was stirred for 3 h at RT and then mixed with diethyl ether (175 ml) and water (115 ml). The phases were separated and the aqueous phase was extracted with diethyl ether (2×75 ml). The combined organic extracts were washed successively with water (100 ml) and sat. NaCl solution (100 ml). The organic phase was dried and concentrated. Compound W was obtained as a yellowish-green oil (3.33 g) and immediately reacted further.
Reaction SMILES: [NH2:1][C:2]([CH2:4][CH2:5][C:6]([O-:8])=O)=[O:3].[NH2:9][OH:10]>O1CCOCC1>[OH:10][NH:9][C:6](=[O:8])[CH2:5][CH2:4][C:2]([NH2:1])=[O:3]
Reactant: NO
Reactant: NC(=O)CCC(=O)[O-]
Solvent: C1COCCO1
Product: NC(=O)CCC(=O)NO

Procedure:
3-Aminocarbonylpropionate 3 (0.1 mmol) was treated with dioxane (1 mL) and hydroxylamine (50% in water, 2 mL) for 1 to 3 days, and then can be purified by preparative reverse-phase (C18) HPLC to afford the desired N-hydroxy-3-aminocarbonylpropionamide.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)[CH2:6][NH:7][C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[H-].[Na+].Br[CH2:26][C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=1[C@H:37]([CH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1)[O:38][CH3:39]>CN(C=O)C>[F:18][C:17]([F:19])([F:20])[C:15]1[CH:14]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:16]=1)[CH2:6][N:7]([CH2:26][C:27]1[CH:32]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:30]=[CH:29][C:28]=1[C@H:37]([CH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1)[O:38][CH3:39])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: Cn1nnc(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: CO[C@H](c1ccc(C(F)(F)F)cc1CBr)C1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@H](c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.1 %

Procedure:
To a solution of N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine (25.7 mg, 0.078 mmol) in DMF (0.1 mL) at room temperature was added sodium hydride (6 mg, 0.2 mmol). The mixture was stirred at room temperature for 1 hour. 2-(Bromomethyl)-1-(cyclopentyl(methoxy)methyl)-4-(trifluoromethyl)benzene (Enantiomer 1 from STEP D, 23.1 mg, 0.066 mmol) in DMF (0.2 mL) was added. The mixture was stirred at room temperature for 2 days. Solvent was removed in vacuo. The residue was purified by chromatography over 12+S Biotage silica column (eluted with 0-25% ethyl acetate in heptane) to afford the title compound (7.5 mg, 19%). 1H NMR (400 MHz, CDCl3) δ ppm 1.04-1.16 (m, 1H) 1.22-1.33 (m, 1H) 1.38-1.50 (m, 3H) 1.51-1.63 (m, 2H) 1.65-1.76 (m, 1H) 2.02-2.14 (m, 1H) 3.07 (s, 3H) 4.19 (d, J=7.88 Hz, 1H) 4.20-4.23 (m, 3H) 4.72 (d, J=2.49 Hz, 2H) 4.76 (d, J=16.18 Hz, 1H) 4.90 (d, J=16.18 Hz, 1H) 7.35 (s, 1H) 7.51-7.58 (m, 2H) 7.66 (s, 2H) 7.78 (s, 1H). MS (ES+) Calc: 595.2, Found: 596.5 (M+1) To a solution of N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine (27.2 mg, 0.084 mmol) in DMF (0.1 mL) at room temperature was added sodium hydride (6 mg, 0.2 mmol). The mixture was stirred at room temperature for 1 hour. 2-(Bromomethyl)-1-(cyclopentyl(methoxy)methyl)-4-(trifluoromethyl)benzene (Enantiomer 2 from STEP D, 24.5 mg, 0.070 mmol) in DMF (0.2 mL) was added. The mixture was stirred at room temperature overnight. Solvent was removed in vacuo. The residue was purified by chromatography over 12+S Biotage silica column (eluted with 0-30% ethyl acetate in heptane) to afford the title compound (18.6 mg, 45%). The residue was purified by chromatography over 12+S Biotage silica column (eluted with 0-30% ethyl acetate in hexanes) to afford a colorless oil (18.6 mg, 45%). 1H NMR (400 MHz, CDCl3) δ ppm 1.04-1.15 (m, 1H) 1.23-1.33 (m, 1H) 1.38-1.63 (m, 5H) 1.66-1.75 (m, 1H) 2.03-2.11 (m, 1H) 3.07 (s, 3H) 4.19 (d, J=7.88 Hz 1H) 4.21 (s, 3H) 4.72 (d, J=2.90 Hz, 2H) 4.76 (d, J=16.18 Hz, 1H) 4.90 (d, J=16.18 Hz, 1H) 7.35 (s, 1H) 7.51-7.58 (m, 2H) 7.66 (s, 2H) 7.77 (s, 1H). MS (ES+) Calc: 595.2, Found: 596.5 (M+1).
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[OH-].[Na+].[CH2:7]([C:10]1[N:11]([CH2:23][CH2:24][CH2:25][CH:26]=O)[C:12]2[C:21]3[N:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:22]=1)[CH2:8][CH3:9]>CO>[CH3:3][O:2][N:4]=[CH:26][CH2:25][CH2:24][CH2:23][N:11]1[C:12]2[C:21]3[N:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:22]=[C:10]1[CH2:7][CH2:8][CH3:9]
Reactant: CCCc1nc2cnc3cccnc3c2n1CCCC=O
Reactant: CON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1nc2cnc3cccnc3c2n1CCCC=NOC
Reaction time: 8 h
Yield: 102 %

Procedure:
Methoxylamine hydrochloride (3.39 g, 40.6 mmol, 2 eq) and 6M sodium hydroxide solution (7.5 mL, 44.7 mmol. 2.2 eq) were added sequentially to a solution of 4-(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyraldehyde (5.73 g, 20.3 mmol, 1 eq) in methanol (80 mL) and stirred overnight. The mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane (100 mL) and water (60 mL). The pH of the mixture was adjusted to 7 and the layers were separated. The aqueous layer was extracted with dichloromethane (2×20 mL) and the combined organics were washed with brine (75 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 6.45 g of 4-(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyraldehyde O-methyloxime as an orange oil with an E/Z ratio of 77:23. The material was used in subsequent steps without any further purification.
Reaction SMILES: C([O-])=O.[NH4+].CN(C)/[CH:7]=[CH:8]/[C:9]1[S:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][C:10]=1[N+:18]([O-])=O>CO.CCOC(C)=O.[Pd]>[S:13]1[C:9]2[CH:8]=[CH:7][NH:18][C:10]=2[CH:11]=[C:12]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(/C=C/N(C)C)s1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cc2[nH]ccc2s1
Temperature: 25 °C

Procedure:
10% Pd/C (0.4 eq.) and ammonium formate (6 eq.) were added to a 0.1M solution of methyl 5-[(E)-2-(dimethylamino)ethenyl]-4-nitrothiophene-2-carboxylate in MeOH/EtOAc 1:1, and the mixture was heated to reflux for 30 min; after cooling to RT the flask was flushed with nitrogen a few times, then the reaction mixture was filtered and the solution evaporated i. vac. The residue was dissolved in EtOAc and washed with water and brine, dried over Na2SO4, and concentrated i. vac. The crude product (50% over two steps) was used as such. 1H-NMR (400 MHz, CDCl3, 300 K, δ) 8.44 (bs, 1H), 7.72 (s, 1H), 7.21 (bs, 1H), 6.50 (bs, 1H), 3.91 (s, 3H); MS (ES+) m/z 182 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:9])[N:4]([CH3:8])[N:5]=[CH:6][CH:7]=1.[CH:10]([C:13]1[CH:14]=[CH:15][C:16]([CH3:26])=[C:17]([CH:25]=1)[O:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([CH3:12])[CH3:11].Cl.FC(F)(F)C1C=CC=C[C:31]=1[O:32]C1CCNCC1>>[CH3:8][N:4]1[C:3](=[O:9])[C:2]([NH:1][C:31]([N:22]2[CH2:23][CH2:24][CH:19]([O:18][C:17]3[CH:25]=[C:13]([CH:10]([CH3:12])[CH3:11])[CH:14]=[CH:15][C:16]=3[CH3:26])[CH2:20][CH2:21]2)=[O:32])=[CH:7][CH:6]=[N:5]1
Reactant: Cc1ccc(C(C)C)cc1OC1CCNCC1
Reactant: Cn1nccc(N)c1=O
Reactant: FC(F)(F)c1ccccc1OC1CCNCC1
Agent: Cl
Product: Cc1ccc(C(C)C)cc1OC1CCN(C(=O)Nc2ccnn(C)c2=O)CC1
Yield: 51 %

Procedure:
Compound 57 is prepared from intermediate 4c and from 4-(5-isopropyl-2-methyl-phenoxy)-piperidine (obtained following the method described for intermediate 1a,) applying synthesis method 7 (yield: 51%).