Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([O:10][C:11]([N:13]1[CH2:16][CH:15]([S:17][C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[N:1]1([C:22]([C:21]2[CH:20]=[CH:19][C:18]([S:17][CH:15]3[CH2:16][N:13]([C:11]([O:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:12])[CH2:14]3)=[CH:26][CH:25]=2)=[O:23])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1CC(Sc2ccc(C(=O)O)cc2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC(Sc2ccc(C(=O)N3CCCC3)cc2)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 97.6 %

Procedure:
Pyrrolidine (0.60 g, 8.4 mmol) was added to a solution of 59B (2.0 g, 6.5 mmol) and DCM (25 mL). The mixture was cooled to 0° C. and then DIPEA and TBTU were added in the given order. The mixture was stirred at 0° C. for 20 min and then at RT for 1.5 h. The solution was washed with aqueous Na2CO3 (1M) and then the organic solution was evaporated. The product was purified by silica-gel chromatography using 1-5% methanol in DCM. There was obtained 2.3 g (98%) of 59C as an oil. 1H NMR (500 MHz, CDCl3): δ 1.42 (s, 9H), 1.89 (m, 4H), 3.41 (m, 2H), 3.62 (m, 2H), 3.86 (m, 2H), 4.04 (m, 1H), 4.34 (m, 2H), 7.19 (d, 2H), 7.45 (d, 2H), MS (APCI+) m/z 363 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[F:16])[CH:12]1[CH2:17][CH:10]([CH2:11]1)[N:9]1[C:5]2=[N:6][C:7]([C:18]([NH2:20])=[O:19])=[CH:8]1.[I:21]N1C(=O)CCC1=O>CN(C=O)C>[F:16][C:15]1[C:2]([Br:1])=[CH:3][C:4]2[C:5]3[N:9]([CH:10]4[CH2:11][CH:12]([C:13]=2[CH:14]=1)[CH2:17]4)[C:8]([I:21])=[C:7]([C:18]([NH2:20])=[O:19])[N:6]=3
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1C1CC2C1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: NC(=O)c1nc2n(c1I)C1CC(C1)c1cc(F)c(Br)cc1-2
Temperature: 70 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
9-bromo-10-fluoro-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7,9,11-pentaene-4-carboxamide (20.00 g, 59.5 mmol) and N-iodosuccinimide (2.00 equiv., 27.60 g, 119 mmol) were dissolved in DMF (300 mL, 5 mL/mmol) and stirred at 70° C. overnight. After 24 hours, the solution was concentrated in vacuo and diluted with water, then triturated for 1 hour and filtered. The solid was redissolved in ethyl acetate, triturated for 1 hour, and filtered to afford 23.93 g (87% yield) of the titled compound as a light orange solid, 1H NMR (400 MHz, DMSO) δ 8.92 (d, J=7.4 Hz, 1H), 7.74 (br s, 1H), 7.37 (d, J=9.5 Hz, 1H), 7.16 (br s, 1H), 5.12 (td, J=6.7, 4.1 Hz, 1H), 3.68 (td, J=7.6, 4.1 Hz, 1H), 3.25-3.11 (m, 2H), 1.78-1.64 (m, 2H).
Reaction SMILES: N([O-])=O.[Na+].FC(F)(F)C([O-])=O.[CH2:12]([O:14][C:15]([C:17]1[CH:18]=[N:19][N:20]2[CH:25]=[CH:24][C:23]([NH3+])=[C:22]([F:27])[C:21]=12)=[O:16])[CH3:13].[BrH:28]>O>[Br:28][C:23]1[CH:24]=[CH:25][N:20]2[N:19]=[CH:18][C:17]([C:15]([O:14][CH2:12][CH3:13])=[O:16])=[C:21]2[C:22]=1[F:27]
Reactant: Br
Reactant: CCOC(=O)c1cnn2ccc([NH3+])c(F)c12
Agent: O=C([O-])C(F)(F)F
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cnn2ccc(Br)c(F)c12
Reaction time: 1 h

Procedure:
NaNO2 (2.26 g, 32.89 mmol) in water (7 mL) was added dropwise at 0° C. to a solution of 3-(ethoxycarbonyl)-4-fluoropyrazolo[1,5-a]pyridin-5-aminium 2,2,2-trifluoroacetate (7 g, 97.5 mmol) in aq.47% HBr (56 mL) and continued stirring at same temperature for 30 min. CuBr (6.29 g, 44 mmol) in aq.47% HBr (56 mL) was added dropwise to above solution at 0° C. and stirring was continued at 28° C. for 1 hr. Reaction mixture was quenched with ice water, extracted into EtOAc, washed it with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude. The crude obtained was purified by column purification (using 60-120 silicagel and 5% EtOAc in Hexane as eluant) to afford ethyl 5-bromo-4-fluoropyrazolo[1,5-a]pyridine-3-carboxylate. NMR (300 MHz, DMSO-d6) δ 9.45-9.43 (d, 1H), 8.51 (s, 1H), 8.33-8.30 (d, 1H), 4.35-4.28 (m, 2H), 1.36-1.31 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:7]([C:8]([O-:10])=[O:9])[C:6]([OH:12])=[CH:5][CH:4]=1.[Na+].[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]([OH:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(O)c(C(=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: COc1ccc(O)c(C(=O)O)c1

Procedure:
In a 200 ml four-necked flask were placed 29.79 g (0.240 mol) of 4-methoxyphenol, 2.05 g (0.018 mol) of DMi and 40 g of xylene, and the solution was heated 4 until reflux began. Afterward, azeotropic dehydration was carried out, while 4.41 g (0.054 mol) of a 49 wt % aqueous NaOH solution was added dropwise over 5 hours. Next, 20 g of xylene was added dropwise, and the solution was allowed to mature under the reflux for 2 hours. It was confirmed that a stoichiometric amount of water was distilled. The reaction solution was put in a 300 ml autoclave, heated up to 160° C., and then allowed to absorb a carbon dioxide gas at 6 kg/cm2G, followed by maturation at the same temperature for 7 hours. In this case, a conversion was 74.9%/NaOH. The reaction solution was slowly cooled to 70° C., and then crystallized at 70° C. for 2 hours. The reaction solution was filtered at the same temperature, and then washed three times with 20 g of xylene to obtain wet sodium 5-methoxysalicylate. According to analysis, the recovery yield of sodium 5-methoxysalicylate was 72.8%/NaOH, and any DMi was not detected. It was confirmed that DMi was completely recovered in a filtrate and a wash liquid in the steps of the heating, the filtration and the washing. The wet product was dissolved in 54 g of water at 60° C., and an extraction operation was carried out twice with 18 g of xylene to obtain an aqueous layer. Xylene dissolved in this aqueous layer was distilled off under reduced pressure, and the aqueous layer was added dropwise to 49 g of a 6% sulfuric acid solution over 2 hours to crystallize. The resulting precipitate was filtered, and then washed three times with 12 g of water. Next, wet 5-methoxysalicylic acid was taken out, and then dried to obtain 6.60 g of 5-methoxysalicylic acid. In this case, a purity was 99.9% or more and a total recovery yield in terms of pure product from the raw material was 72.7%/NaOH.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9]1)C1C=CC=CC=1>CO.C(O)(=O)C.[Pd]>[C:18]([O:17][C:15]([NH:14][CH2:13][CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCC1CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCC1CCNC1
Reaction time: 48 h

Procedure:
1-Benzyl-3-(RS)-(N-tert-butoxycarbonylaminomethyl)pyrrolidine (22.2 g, 0.76 mol) was dissolved in a mixture of methanol and acetic acid (1:1, 100 mL) and added to a Parr flask charged with palladium on carbon (10%, 4 g) suspended in methanol and acetic acid (1:1, 100 mL). The flask was transferred to the Parr reduction apparatus and the suspension shaken under an atmosphere of hydrogen at 60 psi for 2 days. The reaction mixture was filtered through a celite plug, eluting with a mixture of methanol/methylene chloride. The solvent was concentrated and the residue co-evaporated with toluene to afford 3-(RS)-(N-tert-butoxycarbonylaminomethyl)pyrrolidine as a colorless oil which was used directly.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([O:34][CH2:35][CH:36]([CH3:38])[CH3:37])[N:20]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([O:34][CH2:35][CH:36]([CH3:38])[CH3:37])[N:20]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1cc(OCc2ccc(-c3cc(OC)ccc3F)c(OCC(C)C)n2)ncn1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(COc3cc(C(CC(=O)O)C4CC4)ncn3)nc2OCC(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(6-((5-(2-fluoro-5-methoxyphenyl)-6-isobutoxypyridin-2-yl)methoxy)pyrimidin-4-yl)propanoate (198 mg) in THF (3.0 mL) and methanol (1.5 mL) was added 1N aqueous sodium hydroxide solution (3.0 mL), and the mixture was stirred at room temperature for 30 min. 1N Hydrochloric acid (3.0 ml) was added to the reaction mixture at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure to give the title compound (180 mg) as a white amorphous solid.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]N)=[CH:5][CH:4]=1)#[N:2].O.S(=O)(=O)(O)[OH:13].N([O-])=O.[Na+]>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:13])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccc(CN)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(CO)cc1
Yield: 51.1 %

Procedure:
p-Cyanobenzylamine (13.2 g), water (54 g), and toluene (20 g) were mixed, and the mixture was stirred with cooling with ice. Concentrated sulfuric acid (14.7 g) was added to the mixture. Subsequently, a 20 wt % aqueous solution (44.9 g) of sodium nitrite was added dropwise to the mixture over one hour. The mixture was stirred at the same temperature for four hours. For the subsequent process, the procedure of Example 1 was repeated, to thereby obtain 6.8 g of p-cyanobenzyl alcohol (yield 51%). The purity of the product was 98%.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:15]4[N:16]=[C:17](S(C)(=O)=O)[N:18]=[CH:19][C:14]=4[C:13](=[O:24])[C:12]([C:25]([NH2:27])=[O:26])=[CH:11]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:37]=[C:38]([NH2:42])[CH:39]=[CH:40][CH:41]=2)[CH2:31][CH2:30]1>CC(O)C>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:15]4[N:16]=[C:17]([NH:42][C:38]5[CH:39]=[CH:40][CH:41]=[C:36]([CH2:35][N:32]6[CH2:31][CH2:30][N:29]([CH3:28])[CH2:34][CH2:33]6)[CH:37]=5)[N:18]=[CH:19][C:14]=4[C:13](=[O:24])[C:12]([C:25]([NH2:27])=[O:26])=[CH:11]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CN1CCN(Cc2cccc(N)c2)CC1
Reactant: CS(=O)(=O)c1ncc2c(=O)c(C(N)=O)cn(-c3ccc4c(c3)CCC4)c2n1
Solvent: CC(C)O
Product: CN1CCN(Cc2cccc(Nc3ncc4c(=O)c(C(N)=O)cn(-c5ccc6c(c5)CCC6)c4n3)c2)CC1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a suspension of 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide (from Example 23 (b), 7 mg) in 1 mL of i-PrOH was added 3-(4-methyl-piperazin-1-ylmethyl)-phenylamine (5 mg). The mixture was stirred at 90° C. for 1 hr. After cooling down, the solvent was evaporated and the product was purified chromatographically (CH2Cl2/CH3OH/NH4OH (10:1:0.1, v/v)). The title compound was obtained as white solid (2.7 mg, 29%). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.39 (br, 1H), 9.34 (s, 1H), 8.76 (s, 1H), 7.48 (br, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.29 (br, 1H), 7.17 (s, 1H), 7.12 (d, J=8.0 Hz, 1H), 6.94 (br, 2H), 5.67 (br, 1H), 3.29 (br, 2H), 3.00 (t, J=7.3 Hz, 2H), 2.92 (t, J=7.3 Hz, 2H), 2.49 (br, 7H), 2.33 (br, 4H), 2.15 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C29H31N7O2: 510.25 (M+H), Found: 510.1.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].NCCC1C2C(=CC=CC=2)NC=1.[Cl:18][CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23]>>[Cl:18][CH2:19][CH2:20][CH2:21][C:22]([N:3]([O:4][CH3:5])[CH3:2])=[O:23]
Reactant: O=C(Cl)CCCCl
Reactant: CNOC
Agent: Cl
Agent: NCCc1c[nH]c2ccccc12
Product: CON(C)C(=O)CCCCl
Reaction time: 1.5 h
Yield: 89.4 %

Procedure:
To a solution of 4-chlorobutyryl chloride (10.0 g in 200 mL of dry methylene chloride) was added 10.4 g of N,O-dimethylhydroxylamine hydrochloride. The mixture was stirred under nitrogen and maintained below 25° C. by cooling in an ice bath as necessary while triethylamine 5 (29.1 mL)was added dropwise over about 20 minutes, resulting in precipitation. After 1.5 hours at room temperature, the mixture was concentrated in vacuo. The residue was partitioned between 100 mL of diethyl ether and 100 mL of saturated aqueous sodium bicarbonate solution. The organic layer was washed with an additional 100 mL of saturated sodium bicarbonate, and the aqueous fractions were back-extracted with ether. The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo to give 10.5 g (90%) of an oil, which had satisfactory purity by 1H NMR (CDCl3). Mass spectrum (PB-NH3 / CI): m/e=166 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:26][CH2:25][C:11]2([O:15][C:14](=[O:16])[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=3)[CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[F:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=1[N:42]=[C:43]=[O:44].O>C(Cl)Cl.CCOC(C)=O>[F:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=1[NH:42][C:43]([N:8]1[CH2:26][CH2:25][C:11]2([O:15][C:14](=[O:16])[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=3)[CH2:12]2)[CH2:10][CH2:9]1)=[O:44]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(Cc1cccc(Br)c1)C(=O)O2
Reactant: O=C=Nc1cc(F)ccc1F
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Nc1cc(F)ccc1F)N1CCC2(CC1)CN(Cc1cccc(Br)c1)C(=O)O2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
The compound A6 (0.50 g, 1.18 mmol) was dissolved in DCM (3 mL) and combined with trifluoroacetic acid (3 mL). The reaction mixture was stirred for 5 min at RT and the solvent was then removed under a vacuum. The residue was combined repeatedly with toluene and the solvent was then removed again. The residue was then combined with sat. aq. NaHCO3 solution and repeatedly extracted with EtOAc. The combined organic phases were dried over Na2SO4 and the solvent was removed under a vacuum. The residue was redissolved in anhydrous THF (5 mL) and combined with a little triethylamine. The reaction mixture was combined with 2,5-difluorophenyl isocyanate (145 μL, 1.23 mmol), stirred for 18 h at RT and combined with water and EtOAc. The organic phase was separated off and the aqueous phase repeatedly extracted with EtOAc. The combined organic phases were washed with sat. aq. NaCl solution, dried over Na2SO4 and the solvent was removed under a vacuum. The residue was purified by column chromatography (SiO2, heptane/EtOAc 2:1). After crystallisation from heptane and DCM, 483 mg (85% of theoretical) of the desired product 3-(3-bromobenzyl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylic acid (2,5-difluorophenyl)amide (29) were obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]23O[CH:10]([C:11]4[C:16]2=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=4)[C:9]([C:22]([O:24][CH3:25])=[O:23])=[C:8]3[C:26]([O:28][CH3:29])=[O:27])=[CH:3][CH:2]=1.FB(F)F.C(OCC)C>C(#N)C>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH:10]=[C:9]([C:22]([O:24][CH3:25])=[O:23])[C:8]=2[C:26]([O:28][CH3:29])=[O:27])=[CH:3][CH:2]=1
Reactant: COC(=O)C1=C(C(=O)OC)C2(c3ccncc3)OC1c1cc(OC)c(OC)cc12
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)c1cc2cc(OC)c(OC)cc2c(-c2ccncc2)c1C(=O)OC
Yield: 72.9 %

Procedure:
1-(4-Pyridyl)- 2,3-bis(methoxycarbonyl)-6,7-dimethoxy-1,4-epoxy-1,4-dihydronaphthalene (3.0 g) and trifluoroborane.diethyl ether (1.95 g) are added to acetonitrile (100 ml), and the mixture is refluxed for 2 hours. The reaction solution is separated with a mixture of chloroform (300 ml) and aqueous sodium hydrogen carbonate solution (50 ml), and the organic layer is further washed with aqueous sodium hydrogen carbonate solution, dried, and concentrated. The resulting residue is washed with a small amount of diethyl ether to give 1-(4-pyridyl)-2,3-bis(methoxy-carbonyl)-6,7-dimethoxynaphthalene (2.1 g) as crystal.
Reaction SMILES: Br[CH:2]([C:4]1[O:5][C:6]2[C:11]([C:12](=[O:21])[C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)=[CH:10][C:9]([F:22])=[CH:8][CH:7]=2)[CH3:3].CS(C)=[O:25]>C(O)CCC>[F:22][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[O:5][C:4]([CH:2]([OH:25])[CH3:3])=[C:13]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[C:12]2=[O:21]
Reactant: CC(Br)c1oc2ccc(F)cc2c(=O)c1-c1cccc(F)c1
Reactant: CS(C)=O
Solvent: CCCCO
Product: CC(O)c1oc2ccc(F)cc2c(=O)c1-c1cccc(F)c1
Temperature: 120 °C
Yield: 64 %

Procedure:
To a solution of 2-(1-bromoethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one (15.0 g, 40.84 mmol) in DMSO (150 ml), n-butanol (7.5 ml) was added and heated to 120° C. for 3 h. The reaction mixture was cooled to RT, quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as an off-white solid (7.90 g, 64%). 1H-NMR (δ ppm, CDCl3, 400 MHz): 7.85 (dd, J=8.1, 3 Hz, 1H), 7.54 (dd, J=9.2, 4.2 Hz, 1H), 7.47-7.37 (m, 2H), 7.15-6.98 (m, 3H), 4.74 (quintet, J=6.8 Hz, 1H), 2.23 (d, J=7.4 Hz, 1H), 1.54 (d, J=6.6 Hz, 3H).
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([NH2:19])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CO>[N:15]1[C:13]2[CH2:14][NH:8][CH2:9][CH2:10][O:11][C:12]=2[N:18]=[C:17]([NH2:19])[CH:16]=1
Reactant: Nc1cnc2c(n1)OCCN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Nc1cnc2c(n1)OCCNC2
Temperature: 50 °C
Reaction time: 1 h
Yield: 34.9 %

Procedure:
A mixture of 8-benzyl-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepin-3-amine (87 mg), 20% Pd(OH)2/C (150 mg) and methanol (2 mL) was stirred under a hydrogen atmosphere at 50° C. for 1 hr. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by recrystallization (ethanol-hexane) to give the title compound (19.7 mg, 35%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][C:10]1[N:15]=[CH:14][C:13]([NH:16][C:17](=[O:21])[C@@H:18]([CH3:20])[NH2:19])=[CH:12][CH:11]=1.C(N(CC)CC)C.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][C:10]1[N:15]=[CH:14][C:13]([N:16]2[C:17](=[O:21])[C@@H:18]([CH3:20])[NH:19][C:30]2=[O:32])=[CH:12][CH:11]=1
Reactant: Cc1cccc(Oc2ccc(NC(=O)[C@@H](C)N)cn2)c1C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(Oc2ccc(N3C(=O)N[C@H](C)C3=O)cn2)c1C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
N1-{6-[(2,3-dimethylphenyl)oxy]-3-pyridinyl}-D-alaninamide (Intermediate 40, 13 mg) was dissolved in dry dichloromethane (2 mL). The reaction mixture (under argon) was cooled down in an ice bath. Triethylamine (38.1 μl, 0.273 mmol) was added. Then a solution of triphosgene in dry dichloromethane (5.41 mg, 0.018 mmol, 0.40 equiv dissolved in 1 mL of DCM) was added dropwise. The reaction mixture was stirred at 0° C., under argon, during 10 min. A saturated aqueous solution of NaHCO3 was added (3 mL) and the aqueous layer was extracted with dichloromethane 4 times (4×4 mL). After drying over sodium sulphate, the solvents were removed under vacuum. The residue was purified by silica gel chromatography (Companion system, 4 g silica cartridge,) with a gradient cyclohexane/ethylacetate from 100:0 to 55:45 during 10 min and 55:45 during 20 min. This afforded the title compound (9 mg)
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][CH2:17]3)=[CH:12][N:11]=2)=[CH:5][C:4]([C:26]2[CH:33]=[N:32][CH:31]=[C:30]([N:34]3[CH2:46][CH2:45][C:44]4[N:43]5[C:38]([CH2:39][CH2:40][CH2:41][CH2:42]5)=[CH:37][C:36]=4[C:35]3=[O:47])[C:27]=2[CH:28]=[O:29])=[CH:3]1.[BH4-].[Na+]>CO>[OH:29][CH2:28][C:27]1[C:26]([C:4]2[CH:5]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:17][CH2:18][N:19]([CH:22]5[CH2:25][O:24][CH2:23]5)[CH2:20][CH2:21]4)=[CH:12][N:11]=3)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)=[CH:33][N:32]=[CH:31][C:30]=1[N:34]1[CH2:46][CH2:45][C:44]2[N:43]3[C:38]([CH2:39][CH2:40][CH2:41][CH2:42]3)=[CH:37][C:36]=2[C:35]1=[O:47]
Reactant: Cn1cc(-c2cncc(N3CCc4c(cc5n4CCCC5)C3=O)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1cc(-c2cncc(N3CCc4c(cc5n4CCCC5)C3=O)c2CO)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37.7 %

Procedure:
A mixture of 112f (130 mg, 0.20 mmol) and NaBH4 (20 mg, 0.5 mmol) in MeOH (5 mL) was stirred at 0° C. for 0.5 h. The mixture was quenched with water and extracted with EtOAc (5 mL×2). The combined EtOAc extract was concentrated under reduced pressure and the residue was purified with reverse-phase prep-HPLC to afford 112 (48 mg, 34%). LCMS: [M+H]+: 637. 1H NMR (500 MHz, DMSO) δ 8.58 (s, 1H), 8.48 (s, 1H), 8.45 (s, 1H), 8.39 (s, 1H), 7.86 (d, J=2.4, 1H), 7.37-7.36 (m, 2H), 7.23-7.21 (m, 1H), 6.02 (s, 1H), 5.02 (s, 1H), 4.54 (t, J=6.5, 2H), 4.45 (t, J=5.5, 2H), 4.36-4.35 (m, 2H), 4.00-3.79 (m, 4H), 3.59 (s, 3H), 3.43-3.41 (m, 1H), 3.07-2.96 (m, 6H), 2.70 (t, J=6.0, 2H), 2.39-2.38 (m, 4H), 1.92-1.90 (m, 2H), 1.75-1.73 (m, 2H).
Reaction SMILES: [CH:1]1([C:4]2[C:9]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[F:17])=[C:8]([F:18])[C:7]([O:19][CH:20]([CH3:22])[CH3:21])=[C:6]([CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([N:30]4[CH:35]=[CH:34][C:33]([C:36]([O:38]C)=[O:37])=[C:32]([CH2:40][CH3:41])[C:31]4=[O:42])[CH2:26][CH2:25]3)[CH:5]=2)[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C(O)C>[CH:1]1([C:4]2[C:9]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[F:17])=[C:8]([F:18])[C:7]([O:19][CH:20]([CH3:22])[CH3:21])=[C:6]([CH2:23][N:24]3[CH2:25][CH2:26][CH:27]([N:30]4[CH:35]=[CH:34][C:33]([C:36]([OH:38])=[O:37])=[C:32]([CH2:40][CH3:41])[C:31]4=[O:42])[CH2:28][CH2:29]3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CCc1c(C(=O)OC)ccn(C2CCN(Cc3cc(C4CC4)c(-c4ccc(F)cc4F)c(F)c3OC(C)C)CC2)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1c(C(=O)O)ccn(C2CCN(Cc3cc(C4CC4)c(-c4ccc(F)cc4F)c(F)c3OC(C)C)CC2)c1=O
Yield: 78.3 %

Procedure:
A mixture of methyl 1-(1-((6-cyclopropyl-2,2′,4′-trifluoro-3-isopropoxybiphenyl-4-yl)methyl)piperidin-4-yl)-3-ethyl-2-oxo-1,2-dihydropyridine-4-carboxylate (161 mg), a 1 M aqueous sodium hydroxide solution (1 mL), and ethanol (2 mL) was stirred at 70 C for 1 hour. The reaction mixture was pH-adjusted to 3 using 1 M hydrochloric acid, followed by extraction with ethyl acetate twice. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized (2-propanol/hexane) to obtain the title compound (123 mg).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]([CH:8]([CH3:10])[CH3:9])[C:5](=[O:7])[N:6]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]N)=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:1][C:2]2[O:3][CH:4]([CH:8]([CH3:10])[CH3:9])[C:5](=[O:7])[N:6]=2)=[CH:14][CH:13]=1
Reactant: CC(C)C1OC(N)=NC1=O
Reactant: NCc1ccc(Cl)cc1
Product: CC(C)C1OC(NCc2ccc(Cl)cc2)=NC1=O

Procedure:
Synthesis was performed from 2-amino-5-isopropyl-1,3-oxazol-4(5H)-one and 4-Chlorobenzylamine according to Method G+H.