Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:18]=[CH:17][O:16][CH:15]=2)=[CH:10][C:9]=1[NH:19][C:20](=[O:32])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:16]1[CH:17]=[CH:18][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:22]([C:24]4[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=4)[C:30]#[N:31])[CH2:21][C:20](=[O:32])[NH:19][C:9]=3[CH:10]=2)=[CH:15]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccoc2)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(C2=Nc3ccc(-c4ccoc4)cc3NC(=O)C2)c1

Procedure:
Prepared from {2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4-furan-3-yl-phenyl}-carbamic acid tert.-butyl ester (Example K9) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow powder (73 mg).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([CH2:12][CH2:13][OH:14])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:15]Br>C(Cl)Cl.C1COCC1>[Br:15][C:11]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][NH:9][C:10]=1[CH2:12][CH2:13][OH:14]
Reactant: BrBr
Reactant: OCCc1cc(-c2ccccc2)n[nH]1
Solvent: ClCCl
Solvent: C1CCOC1
Product: OCCc1[nH]nc(-c2ccccc2)c1Br
Reaction time: 2 h
Yield: 93.3 %

Procedure:
2-(3-Phenyl-1H-pyrazol-5-yl)ethanol (664 mg, 3.53 mmol) was dissolved in dry DCM (40 mL) and THF (10 mL). The reaction was cooled in an ice bath and Br2 (363 μL, 7.06 mmol), pre-dissolved in DCM (3 mL), was added slowly dropwise via addition funnel. The reaction was stirred for 2 h in an ice bath, then the reaction was quenched by the addition of Na2SO3 (20 mL of 10% solution; the reaction went from reddish-brown to clear and some bubbling was observed). The reaction was extracted (100 mL each of H2O and DCM). The aqueous layer was extracted again with DCM (100 mL). The combined organic layer was back extracted again with H2O (200 mL). The organic layer was dried and concentrated to yield the title compound (880 mg) as a light yellow solid. LCMS m/z=267.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.78 (t, J=7.14 Hz, 2H), 3.66 (t, J=7.14 Hz, 2H), 7.35-7.42 (m, 1H), 7.43-7.51 (m, 2H), 7.72-7.84 (m, 2H).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].Br[CH2:7]/[CH:8]=[CH:9]/[CH2:10]Br>C1(C)C=CC=CC=1>[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:7]/[CH:8]=[CH:9]/[CH2:10][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH3:2]
Reactant: BrC/C=C/CBr
Reactant: CCNCC
Solvent: Cc1ccccc1
Product: CCN(CC)C/C=C/CN(CC)CC
Reaction time: 4 h
Yield: 108.9 %

Procedure:
Diethylamine (1.5 g, 20 mmol) in toluene (50 ml) was added to a stirred solution of (E)-1,4-dibromobut-2-ene (2.14 g, 10 mmol) in toluene (50 ml) at room temperature, and the solution was stirred for 4 h. The white precipitate formed was filtered off, washed with ether (2×20 ml), and dissolved in hot aqueous ethanol. The solution was allowed to cool and acetone was added. The white precipitate formed was filtered off and washed with acetone to yield (E)-N,N,N',N'-tetraethyl-1,4-diaminobut-2-ene (TED) dihydrobromide (2.16 g, 60%). δH (90 MHz, D2O) 1.10 (12H, t), 3.15 (8H, q), 3.98 (4H, m) and 5.90 (2H, m).
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[C@@H:18]([CH2:19][CH2:20][C@@H:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[OH:22])[C:17](=[O:30])[N:16]2[C:31]2[CH:36]=[CH:35][C:34]([C:37]#[C:38][CH2:39][NH:40][S:41]([CH3:44])(=[O:43])=[O:42])=[CH:33][CH:32]=2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.Cl>C1COCC1>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C@@H:21]([OH:22])[CH2:20][CH2:19][C@H:18]2[C:17](=[O:30])[N:16]([C:31]3[CH:36]=[CH:35][C:34]([C:37]#[C:38][CH2:39][NH:40][S:41]([CH3:44])(=[O:43])=[O:42])=[CH:33][CH:32]=3)[C@@H:15]2[C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)=[CH:24][CH:25]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@@H]2[C@@H](CC[C@H](O)c3ccc(F)cc3)C(=O)N2c2ccc(C#CCNS(C)(=O)=O)cc2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CS(=O)(=O)NCC#Cc1ccc(N2C(=O)[C@H](CC[C@H](O)c3ccc(F)cc3)[C@H]2c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 10 mg of N-[3-(4-{(2S,3R)-2-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-1-yl}phenyl)prop-2-yn-1-yl]methanesulfonamide in 0.5 mL THF was added 0.5 mL of 2N aq. HCl. The resulting mixture was stirred at room temperature for 1 hr at which time the volatiles were removed under vacuum. The residue was purified by prep. Tlc eluting with CH2Cl2/MeOH (9/1) followed by further purification by prep. Tlc eluting with CH2Cl2/MeOH (95/5) afforded the title compound. m/z (ES) 544.9 (M+Na+), 523 (MH+), 505 (M−H2O+).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C@@H:8]([C@@H:17]1[C@@H:21]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH2:20][N:19]([C:30]([C:32]2[CH:37]=C(C)N=[N:34][CH:33]=2)=[O:31])[CH2:18]1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)(C)(C)C.C(O)(=O)C.CC[CH2:47][CH2:48][N+:49](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C@H:8]([C@@H:17]2[C@@H:21]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[CH2:20][N:19]([C:30]([C:32]3[CH:33]=[N:34][C:48]([CH3:47])=[N:49][CH:37]=3)=[O:31])[CH2:18]2)[CH2:7][OH:6])=[N:11][CH:12]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: Cc1cc(C(=O)N2C[C@H]([C@H](CO[Si](C)(C)C(C)(C)C)Oc3ccc(Cl)cn3)[C@@H](c3ccc(Cl)c(Cl)c3)C2)cnn1
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1ncc(C(=O)N2C[C@H]([C@H](CO)Oc3ccc(Cl)cn3)[C@@H](c3ccc(Cl)c(Cl)c3)C2)cn1
Temperature: 25 °C
Yield: 91 %

Procedure:
To a solution of [(3R,4S)-3-[(R)-2-(tert-butyl-dimethyl-silanyloxy)-1-(5-chloro-pyridin-2-yloxy)-ethyl]-4-(3,4-dichloro-phenyl)-pyrrolidin-1-yl]-(6-methyl-pyridazin-4-yl)-methanone (0.074 g, 0.119 mmol) dissolved in THF (4 mL) was added 0.014 mL (0.24 mmol) of acetic acid and 0.119 mL of TBAF (1.0M in THF). The reaction mixture was stirred over night at room temperature. The mixture was diluted with ethyl acetate and washed with water and aq. sodium bicarbonate solution subsequently. The separated organic phase was dried over sodium sulfate and concentrated in vaccuo after filtration. The residue was purified by TLC (SiO2, MeOH/DCM, 1:10) yielded 55 mg (91%) of the title compound as a light yellow oil. ES-MS m/e: 507.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Cl)[N:7]=1.Cl.[NH2:12][C@H:13]([CH:28]1[CH2:30][CH2:29]1)[C:14]1([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:15]1.CCN(C(C)C)C(C)C>C(C#N)(C)=O.CCOC(C)=O>[CH2:20]([O:19][C:18](=[O:27])[NH:17][C:14]1([C@H:13]([NH:12][C:6]2[CH:5]=[N:4][C:3]([C:9]#[N:10])=[C:2]([Cl:1])[N:7]=2)[CH:28]2[CH2:29][CH2:30]2)[CH2:15][CH2:16]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: N[C@H](C1CC1)C1(NC(=O)OCc2ccccc2)CC1
Reactant: N#Cc1ncc(Cl)nc1Cl
Agent: CC(=O)C#N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ncc(N[C@H](C2CC2)C2(NC(=O)OCc3ccccc3)CC2)nc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.4 %

Procedure:
To a mixture of 3,5-dichloropyrazine-2-carbonitrile (208 mg, 1.19 mmol) and (R)-benzyl 1-(amino(cyclopropyl)methyl)cyclopropylcarbamate HCl salt (350 mg, 1.19 mmol) in AcCN (2 mL) was added DIPEA (0.467 mL, 2.62 mmol). After stirring at room temperature for 3 h, it was diluted with EtOAc, washed with sat. NaHCO3, organic layer was separated and washed with brine, dried and concentrated to give (R)-benzyl-1-((6-chloro-5-cyanopyrazin-2-ylamino)(cyclopropyl)methyl)cyclopropylcarbamate (480 mg).
Reaction SMILES: CO[N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:7]([OH:19])[CH:6]=1.Cl>C(O)C.[Pd]>[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:7]([OH:19])[CH:6]=1
Reactant: CON=Cc1ccc(OCCN2CCCC2)c(O)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCc1ccc(OCCN2CCCC2)c(O)c1
Reaction time: 3 h
Yield: 105.8 %

Procedure:
An amount of 3-Hydroxy-4-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde O-methyl-oxime (50 mg, 0.18 mmol) is dissolved in ethanol (10 mL). Then hydrogen chloride (0.130 mL) is added, followed by 10% Pd/C (5.0 mg). After hydrogenation at 35 psi for 3 h, the solution is filtered through Celite and evaporated to dryness. The residue is recrystallized from ethyl acetate to give 45 mg of crude product as a white solid. MS (ESI) m/z 283.1 (M+1)
Reaction SMILES: [CH3:1][O:2][CH:3]([O:26][CH3:27])[CH2:4][O:5][C:6]1[C:7]([CH3:25])=[C:8]([C:16]([C:18]2[CH:19]=[N:20][N:21]([CH3:24])[C:22]=2[OH:23])=[O:17])[CH:9]=[CH:10][C:11]=1[S:12]([CH3:15])(=[O:14])=[O:13].C(N(CC)CC)C.[CH3:35][CH2:36][S:37][C:38](Cl)=[O:39].C(OCC)(=O)C>C1COCC1>[CH3:27][O:26][CH:3]([O:2][CH3:1])[CH2:4][O:5][C:6]1[C:7]([CH3:25])=[C:8]([C:16]([C:18]2[CH:19]=[N:20][N:21]([CH3:24])[C:22]=2[O:23][C:38]([S:37][CH2:36][CH3:35])=[O:39])=[O:17])[CH:9]=[CH:10][C:11]=1[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: COC(COc1c(S(C)(=O)=O)ccc(C(=O)c2cnn(C)c2O)c1C)OC
Reactant: CCSC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCSC(=O)Oc1c(C(=O)c2ccc(S(C)(=O)=O)c(OCC(OC)OC)c2C)cnn1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The crude 5-hydroxy-1-methylpyrazol-4-yl 3-(2,2-dimethoxyethoxy)-2-methyl-4-(methylsulfonyl)phenyl ketone obtained in the above step (3) was dissolved in anhydrous THF (10 mL), and triethylamine (250 mg) and, 96% S-ethyl chlorothiolformate (200 mg) were added, followed by stirring for 1 hour at room temperature. Ethyl acetate (200 mL) was added to the obtained reaction mixture, and the mixture was washed twice with a saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to obtain the desired product (150 mg).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]([N:11]1[C:15]2[C:16](Cl)=[N:17][N:18]([CH3:21])[C:19](=[O:20])[C:14]=2[N:13]=[CH:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)C>[CH2:4]([N:11]1[C:15]2[C:16]([N:2]([CH3:3])[CH3:1])=[N:17][N:18]([CH3:21])[C:19](=[O:20])[C:14]=2[N:13]=[CH:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Cn1nc(Cl)c2c(ncn2Cc2ccccc2)c1=O
Reactant: CNC
Solvent: CCO
Product: CN(C)c1nn(C)c(=O)c2ncn(Cc3ccccc3)c12
Temperature: 130 °C

Procedure:
A 2 ml aqueous solution of 50% dimethylamine was added to a 2 ml ethanol solution of 0.138 g of 1-benzyl-7-chloro-5-methyl-1,5-dihydroimidazo[4,5-d]pyridazin-4-one, and the mixture was heated at 130° C. for 72 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.139 g of the title compound was obtained from the fraction eluted with methanol-ethyl acetate (1:19).
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:7]([OH:9])=O)[CH3:6])(=[O:3])[CH3:2].N1C=CC=CC=1.[C:16]([O:19][CH2:20][CH3:21])(=[O:18])C>C1COCC1.CN(C)C1C=CN=CC=1>[C:1]([NH:4][CH:5]([CH3:6])[C:7](=[O:9])[C:16]([O:19][CH2:20][CH3:21])=[O:18])(=[O:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CC(=O)N[C@@H](C)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)C(=O)C(C)NC(C)=O
Temperature: 0 °C

Procedure:
52 g (396 mmol) of acetylalanine were dissolved in 800 ml of THF, and 45 mg (0.4 mmol) of 4-dimethylaminopyridine and 96 ml (1188 mmol) of pyridine were added. The mixture was heated to reflux, and 88 ml (792 mmol) of ethyl oxalyl chloride were added dropwise over a period of 45 min. The mixture was stirred at reflux for a further 3 h. The reaction mixture was added to ice-water, ethyl acetate was added and the mixture was extracted. The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator. The crude mixture was reacted further without any further purification.
Reaction SMILES: [CH2:1]([N:8]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:9]([CH2:13][O:14][CH:15]([F:17])[F:16])[C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[F:40][C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][C:48]=1[F:49])[CH2:44][NH2:45]>C1COCC1.C(OCC)(=O)C>[CH2:18]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:9]([CH2:13][O:14][CH:15]([F:16])[F:17])[C:10]([NH:45][CH2:44][C:43]1[CH:46]=[CH:47][C:48]([F:49])=[C:41]([F:40])[CH:42]=1)=[O:12])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1ccc(F)c(F)c1
Reactant: O=C(O)C(COC(F)F)N(Cc1ccccc1)Cc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(NCc1ccc(F)c(F)c1)C(COC(F)F)N(Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 77.5 %

Procedure:
To a solution of 2-(dibenzylamino)-3-(difluoromethoxy)propanoic acid (280 mg, 0.835 mmol) and triethylamine (338 mg, 3.34 mmol) in THF (5 mL) at −5° C., isobutyl chloroformate (119.8 mg, 0.876 mmol) was added dropwise. After 20 minutes, 3,4-difluorobenzylamine (131.3 mg, 0.919 mmol) was added and the reaction mixture allowed to warm up to 0° C. for another hour. The mixture was then diluted with ethyl acetate and washed with water, 0.5 N HCl and Brine. The organic layer was dried over magnesium sulphate, concentrated with silica gel and purified by column chromatography, eluting with 10˜20% ethyl acetate in hexanes, to give 2-dibenzylamino-N-(3,4-difluoro-benzyl)-3-difluoromethoxy-propionamide (298 mg, 77.5%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ(ppm) 7.56 (t, 1H), 6.82-7.38 (m, 13H), 6.60 (wt, 1H), 4.58 (dd, 1H), 4.37 (m, 3H), 3.90 (d, 2H), 3.73 (d, 2H) and 3.70 (m, 1H).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[C:5]1=[O:14])[C:2]#[CH:3].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][C:17]=1[Cl:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CN(C=O)C.[Cu]I.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:15][C:16]1[CH:21]=[C:20]([C:3]#[C:2][CH2:1][N:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:13])[C:5]2=[O:14])[CH:19]=[CH:18][C:17]=1[Cl:23]
Reactant: Clc1ccc(I)cc1Cl
Reactant: C#CCN1C(=O)C(=O)c2ccccc21
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1C(=O)N(CC#Cc2ccc(Cl)c(Cl)c2)c2ccccc21
Reaction time: 0.08 h

Procedure:
To a mixture of 1-prop-2-yn-1-yl-1H-indole-2,3-dione (190 mg, 1.03 mmol), 1,2-dichloro-4-iodobenzene (420 mg, 1.54 mmol), copper(I) iodide (11.0 mg, 0.06 mmol) and triphenylphosphine (40.0 mg, 0.15 mmol) in degassed DMF (24 mL) was added triethyl-amine (307 μL, 2.15 mmol). The reaction was stirred for 5 minutes and Pd(OAc)2 (13.0 mg, 0.06 mmol) was then added. The reaction was stirred at room temperature for 2 days, concentrated in vacuo, dissolved in EtOAc and washed with saturated NaHCO3(aq) (1×). The layers were separated and the aqueous layer was extracted with additional EtOAc (2×).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:27])[C:5]2=[C:6]([CH2:8][C@H:9]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3Br)[NH:10]/[C:11]/2=[N:12]\[O:13][CH2:14][C:15]([O:17]C)=[O:16])[N:7]=1.[CH3:28][O:29][C:30]1[N:35]=[C:34](B2OCCN(C3C=CC=CC=3)CCO2)[CH:33]=[CH:32][CH:31]=1.C([O-])([O-])=O.[Na+].[Na+]>CC(N(C)C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[N:3]=[C:4]([CH3:27])[C:5]2=[C:6]([CH2:8][C@H:9]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[C:34]3[CH:33]=[CH:32][CH:31]=[C:30]([O:29][CH3:28])[N:35]=3)[NH:10]/[C:11]/2=[N:12]\[O:13][CH2:14][C:15]([OH:17])=[O:16])[N:7]=1
Reactant: COC(=O)CO/N=C1\N[C@@H](c2ccc(F)cc2Br)Cc2nc(N)nc(C)c21
Reactant: COc1cccc(B2OCCN(c3ccccc3)CCO2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Product: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/OCC(=O)O)N2)n1
Temperature: 85 °C
Yield: 30.9 %

Procedure:
A mixture of (R,Z)-methyl 2-(2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)acetate (105c, 175 mg, 0.4 mmol), 2-(6-methoxypyridin-2-yl)-6-phenyl-1,3,6,2-dioxazaborocane (298 mg, 1.0 mmol), Pd(dppf)2Cl2 (32.5 mg, 0.04 mmol), 2N Na2CO3 (1.0 mL, 2.0 mmol) in DMA (3 mL) was degassed with N2 and heated at 85° C. for over night. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate and filtered through celite. The filtrate was concentrated to afford brown oil which was purified by preparative LCMS to afford (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)acetic acid (105d, 56 mg, 31%) as white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.79 (s, 3H) 3.16 (dd, J=17.05, 10.48 Hz, 1H) 3.45 (dd, J=17.05, 3.92 Hz, 1H) 3.88 (s, 3H) 4.59 (d, J=3.03 Hz, 2H) 4.96 (dd, J=10.36, 3.79 Hz, 1H) 5.90 (brs, 1H) 6.76 (d, J=8.34 Hz, 1H) 7.02 (d, J=6.82 Hz, 1H) 7.14 (dd, J=9.09, 2.78 Hz, 1H) 7.19 (td, J=8.34, 2.78 Hz, 1H) 7.62 (dd, J=8.59, 5.56 Hz, 1H) 7.68 (dd, J=8.34, 7.33 Hz, 1H). MS (ES) [M+H] calculated for C22H22FN6O4, 453.16. found 453.30.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]2[CH:14]=[CH:15][C:16](=O)[N:17](C)[CH:18]=2)=[CH:4][N:3]=1.[Cl:21]C1N=CC(C(=CN(C)C)C(C2OC=CC=2)=O)=CC=1.NC(N)=N>>[Cl:21][C:16]1[N:17]=[CH:18][C:13]([C:5]2[C:6]([C:8]3[O:9][CH:10]=[CH:11][CH:12]=3)=[N:7][C:2]([NH2:1])=[N:3][CH:4]=2)=[CH:14][CH:15]=1
Reactant: Cn1cc(-c2cnc(N)nc2-c2ccco2)ccc1=O
Reactant: CN(C)C=C(C(=O)c1ccco1)c1ccc(Cl)nc1
Agent: N=C(N)N
Product: Nc1ncc(-c2ccc(Cl)nc2)c(-c2ccco2)n1

Procedure:
The process for preparing 5-[2-amino-4-(2-furyl)pyrimidin-5-yl]-1-methylpyridin-2(1H)-one disclosed in patent document 1 is, as shown in the reaction scheme below, a method of allowing 2-(6-chloro-3-pyridyl)-3-dimethylamino-1-(2-furyl)-2-propene-1-one to react with guanidine to afford 5-(6-chloro-3-pyridyl)-4-(2-furyl)-2-pyrimidinylamine, oxidizing this to afford 5-[2-amino-4-(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone, and then methylating this.
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[F:34][C:35]([F:53])([F:52])[C:36]([C:39]1[CH:48]=[CH:47][C:46]2[CH2:45][C@H:44]([C:49]([OH:51])=O)[CH2:43][CH2:42][C:41]=2[N:40]=1)([CH3:38])[CH3:37].Cl.[NH2:55][C@@H:56]([C:58]1[C:63]([F:64])=[CH:62][C:61]([NH:65][S:66]([CH3:69])(=[O:68])=[O:67])=[C:60]([CH3:70])[CH:59]=1)[CH3:57]>CN1CCCC1=O>[F:64][C:63]1[CH:62]=[C:61]([NH:65][S:66]([CH3:69])(=[O:68])=[O:67])[C:60]([CH3:70])=[CH:59][C:58]=1[C@H:56]([NH:55][C:49]([CH:44]1[CH2:43][CH2:42][C:41]2[N:40]=[C:39]([C:36]([CH3:38])([CH3:37])[C:35]([F:53])([F:34])[F:52])[CH:48]=[CH:47][C:46]=2[CH2:45]1)=[O:51])[CH3:57]
Reactant: CC(C)(c1ccc2c(n1)CC[C@@H](C(=O)O)C2)C(F)(F)F
Reactant: Cc1cc([C@@H](C)N)c(F)cc1NS(C)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1cc([C@@H](C)NC(=O)C2CCc3nc(C(C)(C)C(F)(F)F)ccc3C2)c(F)cc1NS(C)(=O)=O
Yield: 45.9 %

Procedure:
A solution of N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (19.8 mg, 0.0522 mmol) and N,N-diisopropylethylamine (28 uL, 0.16 mmol) in N-methylpyrrolidinone (300 uL) was added to (R)-2-(1,1,1-trifluoro-2-methylpropan-2-yl)-5,6,7,8-tetrahydroquinoline-6-carboxylic acid (15 mg, 0.052 mmol) in a 2 mL vial, and the mixture stirred at room temperature for 1 h, before a solution of (R)—N-(4-(1-aminoethyl)-5-fluoro-2-methylphenyl)methanesulfonamide hydrochloride (18 mg, 0.063 mmol) in N-methylpyrrolidinone (200 uL) was added. After 18 h the mixture was filtered and purified by reverse-phase HPLC (30-75% MeCN in 10 mM Et2NH/H2O) to afford the amide as a solid (12.3 mg, 46%). 1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.41 (app dd, J=7.7, 12.0 Hz, 1H), 7.53 (app dd, J=3.3, 8.1 Hz, 1H), 7.35 (d, J=8.1 Hz, 1H), 7.22 (d, J=8.5 Hz, 1H), 7.07 (d, J=11.6 Hz, 1H), 5.09 (app hextet, J=7.3 Hz, 1H), 3.01 (s, 3H), 2.92-2.78 (m, 4H), 2.71-2.61 (m, 1H), 2.26 (s, 3H), 2.06-1.97 (m, 1H), 1.87-1.69 (m, 1H), 1.53 (s, 3H), 1.35 (d, J=7.1 Hz, 3H); m/z=516.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][CH3:12])[N:9]=[CH:10][C:5]2=[C:4]([N:13]2[CH2:19][CH:18]3[O:20][CH:15]([CH2:16][CH2:17]3)[CH2:14]2)[N:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][CH:23]=1>C1(C)C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:15]12[O:20][CH:18]([CH2:17][CH2:16]1)[CH2:19][N:13]([C:4]1[N:3]=[C:2]([C:25]3[CH:26]=[CH:27][C:22]([NH2:21])=[CH:23][CH:24]=3)[N:7]=[C:6]3[N:8]([CH2:11][CH3:12])[N:9]=[CH:10][C:5]=13)[CH2:14]2
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: CCn1ncc2c(N3CC4CCC(C3)O4)nc(Cl)nc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(N)cc3)nc21
Temperature: 120 °C

Procedure:
A mixture of 3-(6-chloro-1-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (0.55 g, 1.9 mmol), 4-aminophenylboronic acid pinacol ester (0.62 g, 2.8 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.22 g, 10 mol %) in toluene/ethanol (1:1, 12 mL) and 2 M aqueous sodium carbonate solution (2 mL) was heated in a 10-20 mL Smith process vial in the microwave reactor for one hour at 120° C. The cooled mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude residue was purified via automated flash chromatography (methanol/chloroform) to provide 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-ethyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline. MS (ES+): 351.0 (M+H)+
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:11][C:10](=[O:12])[NH:9][CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:7]=1[C:20]([OH:22])=O.[C:23]1([CH2:29][CH2:30][CH2:31][NH2:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN=C=NCCCN(C)C.Cl>ClCCl>[C:23]1([CH2:29][CH2:30][CH2:31][NH:32][C:20]([C:7]2[CH:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[NH:9][C:10](=[O:12])[NH:11][C:6]=2[CH2:5][O:4][CH2:3][CH2:2][Cl:1])=[O:22])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C1NC(COCCCl)=C(C(=O)O)C(c2cccc(Cl)c2)N1
Reactant: NCCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C1NC(COCCCl)=C(C(=O)NCCCc2ccccc2)C(c2cccc(Cl)c2)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
205 mg (0.594 mmol) of 6-(2-chloroethoxymethyl)-4-(3-chlorophenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid and 96.4 mg (0.713 mmol) of 3-phenylpropylamine were dissolved in 10 ml of dichloromethane. 171 mg (0.891 mmol) of WSC hydrochloride was added to the obtained solution under cooling with ice, and they were stirred at room temperature overnight. After the concentration under reduced pressure, the reaction mixture was diluted with ethyl acetate and then washed with 1 N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (dichloromethane/methanol=50/1 to 30/1) to obtain the title compound.