Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].II.[Cl:4][C:5]1[CH:6]=[C:7](Br)[CH:8]=[CH:9][C:10]=1[Cl:11].ClC1C=C(Br)C=CC=1Cl.C(OCC)C.[CH3:27][N:28]1[CH2:33][CH:32]=[C:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29]1>C(OCC)C.O>[Cl:4][C:5]1[CH:6]=[C:7]([CH:32]2[CH:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33]2)[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: Clc1ccc(Br)cc1Cl
Reactant: CCOC(=O)C1=CCN(C)CC1
Agent: II
Agent: [Mg]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C1CCN(C)CC1c1ccc(Cl)c(Cl)c1
Temperature: 37.5 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To a suspension of magnesium (10.76 g) in diethyl ether (110 mL) was added a trace amount of iodine. About 1/10 amount of a solution of 3,4-dichlorobromobenzene (100 g) in diethyl ether (110 ml) was added slowly at 35-40° C., and the mixture was vigorously stirred until the reaction started. Once the initiation was occurred, the rest of 3,4-dichlorobromobenzene/diethyl ether solution was added slowly with cooling to maintain the reaction temperature at 35-40° C. When everything was added, and the mixture was stirred at 40° C. for 1 hr, then cooled to 0° C. To the reaction mixture was added copper iodide(I) (12.6 g), and the compound (56.2 g) obtained in step 1 was slowly added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 1 hr, and further at room temperature for 1 hr. The reaction mixture was poured into water (40 mL), diethyl ether (500 mL) was added, and the precipitate was removed by decantation. The reaction solution was washed with aqueous ammonium chloride solution and saturated brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 20% ethyl acetate/hexane→>2.5% aqueous ammonia/17.5% methanol/ethyl acetate) to give crude ethyl 3-(3,4-dichlorophenyl)-1-methylpiperidine-4-carboxylate (cis/trans mixture) (75.5 g) as a brown oil.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[O:24][C:25]1[CH:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=1)[NH2:20].CN1CCCC1=O.C(=O)([O-])O.[Na+]>O>[O:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:9]1[NH:10][C:3]2[C:2]([NH:20][C:19]3[CH:21]=[CH:22][C:23]([O:24][C:25]4[CH:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=4)=[C:17]([CH3:16])[CH:18]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=1
Reactant: Cc1ccc(Oc2ccc(N)cc2C)cn1
Reactant: Clc1ncnc2cc(-c3ccco3)[nH]c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc(Oc2ccc(Nc3ncnc4cc(-c5ccco5)[nH]c34)cc2C)cn1
Temperature: 140 °C
Reaction time: 2 h
Yield: 57.3 %

Procedure:
A mixture of 4-chloro-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine (110 mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (161 mg) and 1-methyl-2-pyrrolidinone (2.5 mL) was stirred at 140° C. for 2 hrs, poured into water (10 mL) and adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate (25 mL×2) and the organic layers were combined and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=1:1→0:1). The object fraction was concentrated under reduced pressure. Chloroform-diisopropyl ether was added to the residue, and the solid was collected by filtration and dried under reduced pressure at 60° C. to give the title compound (114 mg).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:17])[C:5]2[CH:11]=[C:10]([C:12]#[CH:13])[C:9](=[O:14])[N:8]([CH2:15][CH3:16])[C:6]=2[N:7]=1.[N-:18]=[N+:19]=[N-:20].[Na+].[Cl-].[NH4+]>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([CH3:17])[C:5]2[CH:11]=[C:10]([C:12]3[NH:20][N:19]=[N:18][CH:13]=3)[C:9](=[O:14])[N:8]([CH2:15][CH3:16])[C:6]=2[N:7]=1
Reactant: C#Cc1cc2c(C)nc(N)nc2n(CC)c1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(=O)c(-c2cnn[nH]2)cc2c(C)nc(N)nc21
Temperature: 120 °C
Reaction time: 48 h
Yield: 5.8 %

Procedure:
Anhydrous DMF (5.0 mL) was added to a flask charged with 2-amino-8-ethyl-6-ethynyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (0.204 g, 0.894 mmol), sodium azide (0.070 g, 1.07 mmol), and ammonium chloride (0.057 g, 1.07 mmol). The reaction was capped under nitrogen and heated to 120° C. After 48 h, the reaction was cooled to room temperature and concentrated in vacuo. The residue was purified on reverse phase HPLC (acetonitrile:water 0.1% TFA, 20-60% gradient). The fractions containing product were collected and concentrated to one half volume and poured into saturated NaHCO3 (50 mL). The aqueous phase was washed trice with ethyl acetate (50 mL) and dried over Na2SO4, filtered, and concentrated in vacuo. The residue was triturated with methylene chloride and ethyl acetate to afford 2-amino-8-ethyl-4-methyl-6-(1H-1,2,3-triazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (14 mg, 6% yield) as a light yellow solid: 1H NMR (400 MHz, DMSO-d6): δ 8.55 (bs, 1H), 8.41 (bs, 1H), 7.32 (bs, 2H), 4.37 (q, J=7.2 Hz, 2H), 2.60 (s, 3H), 1.21 (t, J=7.2 Hz, 3H); MS (EI) for C12H13N7O: 272.0 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-])=O)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].C(O)(=O)C>[Fe].C(O)C>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4]
Reactant: COC(=O)c1[nH]c2ccccc2c1Oc1ccccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)c1[nH]c2ccccc2c1Oc1ccccc1N
Reaction time: 3 h

Procedure:
A mixture of 3.12g of methyl-3-[o-nitrophenoxy]-indole-2-carboxylate, 10g of 40 mesh iron filings, 5ml of 5% aqueous acetic acid and 300ml of ethanol was refluxed with stirring for 3 hours. The mixture was filtered and concentrated to a solid. Recrystallization from ethanol gave analytical material, mp. 183°-4°.
Reaction SMILES: [C:1]1([C:7]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]4)=[CH:22][CH:21]=3)=[N:18][C:10]3[O:11][CH2:12][C:13]4[N:14]([CH:15]=[N:16][N:17]=4)[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:38]N1C(=O)CCC1=O>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[C:33]([O:32][C:31](=[O:37])[NH:30][C:26]1([C:23]2[CH:24]=[CH:25][C:20]([C:19]3[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][C:9]4[N:14]5[C:15]([Br:38])=[N:16][N:17]=[C:13]5[CH2:12][O:11][C:10]=4[N:18]=3)=[CH:21][CH:22]=2)[CH2:27][CH2:28][CH2:29]1)([CH3:34])([CH3:36])[CH3:35]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3cnnc3CO4)cc2)CCC1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(Br)nnc3CO4)cc2)CCC1
Yield: 68.5 %

Procedure:
A mixture of tert-butyl 1-(4-(8-phenyl-4H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]oxazin-7-yl)phenyl)cyclobutylcarbamate (200 mg, 0.404 mmol) and 1-bromopyrrolidine-2,5-dione (114.9275 mg, 0.646 mmol) in DCM (12 ml) and CCl4 (18 ml) was heating at 50 degree for 24 h. The mixture was concentrated and the residue was partitioned between ethyl acetate (40 ml) and water (40 ml). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (30 ml). The combined organic phase was washed with water (50 ml) brine (30 ml) and concentrated to give product 159 mg. 1H NMR (500 MHz, CDCl3): 8.55 (s, 1H), 7.22-7.35 (m, 9H), 5.58 (s, 2H), 5.1 (br, 1H), 2.4-2.5 (m, 4H), 2.01-2.11 (m, 1H), 1.79-1.89 (m, 1H), 1.24-1.43 (br, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.CN1CCOCC1>CN(C)C=O>[Br:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:6])[C:11]([OH:13])=[O:12]
Reactant: C1CCNC1
Reactant: O=C(O)c1ccc(C(=O)O)c(Br)c1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(C(=O)N2CCCC2)c(Br)c1

Procedure:
100 g (0.388 mol) of 2-bromoterephthalic acid is dissolved in 700 mL of N,N-dimethylformamide and slowly combined with 69.2 g (0.427 mol) of N,N′-carbonyldiimidazole with stirring. After total dissolution, the mixture is stirred for 15 minutes at ambient temperature and then 48.5 mL (0.582 mol) of pyrrolidine and 93.9 mL (0.854 mol) of N-methylmorpholine are slowly added dropwise one after the other. The mixture is stirred for 2.5 days at ambient temperature and then concentrated in vacuo. The residue is combined with distilled water and acidified with 2 molar hydrochloric acid solution. The aqueous phase is extracted with ethyl acetate. The precipitate formed is suction filtered and dried at 40° C. Yield: 29.4 g (25%); Rf value: 0.30 (silica gel; dichloromethane/ethanol=9:1); C12H12BrNO3 (298.14); mass spectrum: (M+H)+=298/300 (bromine isotope).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][NH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH3:27][N:28]=[C:29]=[O:30].N1C=CC=N1>CN(C)C=O.C(OCC)(=O)C>[CH3:27][NH:28][C:29]([N:18]1[CH:19]=[CH:20][C:16]([NH:15][C:13](=[O:14])[C@@H:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:2]([Cl:1])[CH:3]=2)[CH2:21][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)=[N:17]1)=[O:30]
Reactant: CN=C=O
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cc[nH]n2)cc1Cl
Agent: c1cn[nH]c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)n1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 60 °C
Yield: 13.7 %

Procedure:
The 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1H-pyrazol-3-yl)-propionamide (prepared in example 2, 115 mg, 0.29 mmol) was dissolved in anhydrous N,N-dimethylformamide (2 mL) and warmed to 60° C. in a sealed vial. Methyl-isocyanate (165 mg, 2.90 mmol) was transferred via syringe to the pyrazole solution. The mixture was heated at 60° C. for 2 h while stirring in the sealed vial. The mixture was diluted with ethyl acetate (25 mL), washed with water (2×15 mL), saturated aqueous brine solution (15 mL), dried over magnesium sulfate and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 15% ethyl acetate/hexanes to 100% ethyl acetate/hexanes) afforded 3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazole-1-carboxylic acid methylamide (18 mg, 14%) as a white powder: ESI-LRMS m/e calcd for C20H25ClN4O4S [M+] 452.1, found 453.2 [M+H+], 395.9 [M−CONCH3+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.04-1.23 (m, 2H, CH2), 1.43-1.97 (m, 8H, 4×CH2), 2.11-2.34 (m, 1H, CH), 2.95 (d, J=4.6 Hz, 3H, NCH3), 3.27 (s, 3H, SO2CH3), 3.65 (t, J=7.5 Hz, 1H, CH), 6.81 (q, J=4.6 Hz, 1H, NH), 6.84 (d, J=2.7 Hz, 1H, Ar), 7.46 (dd, Jo=8.2, Jm=1.7 Hz, 1H, Ar), 7.60 (d, Jm=1.7 Hz, 1H, Ar), 8.04 (d, Jo=8.2 Hz, 1 H, Ar), 8.07 (d, J=2.7 Hz, 1H, Ar), 8.32 (s, 1H, NH).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[C:26]([C:28]1[N:33]=[C:32]2[NH:34][CH:35]=[C:36]([CH:37]=O)[C:31]2=[CH:30][CH:29]=1)#[CH:27]>CO.N1CCCCC1>[C:26]([C:28]1[N:33]=[C:32]2[NH:34][CH:35]=[C:36](/[CH:37]=[C:7]3\[O:8][C:4]4[C:3]([CH2:12][N:13]5[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]5)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=4[C:6]\3=[O:9])[C:31]2=[CH:30][CH:29]=1)#[CH:27]
Reactant: C#Cc1ccc2c(C=O)c[nH]c2n1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Solvent: C1CCNCC1
Solvent: CO
Product: C#Cc1ccc2c(/C=C3\Oc4c(ccc(O)c4CN4CCN(C(=O)OC(C)(C)C)CC4)C3=O)c[nH]c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.017 g, 0.049 mmol) obtained in Example A16, Step 1 in methanol (2.0 mL) was added with 6-ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (0.007 g, 0.041 mmol). Then, the mixture was added with 5 drops of piperidine, and then the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and then the residue was washed with methylene chloride to obtain tert-butyl (Z)-4-({2-[(6-ethynyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.015 g, 60%).
Reaction SMILES: [CH3:1][C:2]1([C:21]([OH:23])=O)[CH2:17][C:10]2([N+:18]([O-:20])=[O:19])[C:11]3[C:16]([CH:3]1[C:4]1[C:9]2=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.CCN=C=NCCCN(C)C.[Br:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]([C:64]2[NH:68][N:67]=[C:66]([NH2:69])[N:65]=2)([CH3:63])[CH3:62])=[CH:57][CH:56]=1>C(#N)C>[Br:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]([C:64]2[N:65]=[C:66]([NH2:69])[N:67]([C:21]([C:2]3([CH3:1])[CH2:17][C:10]4([N+:18]([O-:20])=[O:19])[C:9]5[C:4]([CH:3]3[C:16]3[C:11]4=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:5][CH:6]=[CH:7][CH:8]=5)=[O:23])[N:68]=2)([CH3:63])[CH3:62])=[CH:57][CH:56]=1
Reactant: CC1(C(=O)O)CC2([N+](=O)[O-])c3ccccc3C1c1ccccc12
Reactant: CC(C)(c1ccc(Br)cc1)c1nc(N)n[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(c1ccc(Br)cc1)c1nc(N)n(C(=O)C2(C)CC3([N+](=O)[O-])c4ccccc4C2c2ccccc23)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.6 %

Procedure:
To a stirred solution of 15-methyl-8-nitrotetracyclo[6.6.2.02,7.09,14]hexadeca-2,4,6,9,11,13-hexaene-15-carboxylic acid (31 mg, 0.10 mmol, prepared according to WO04009017), 1-hydroxybenzotriazole (20 mg, 0.15 mmol), and N-ethyl-N,N-diisopropylamine (0.15 mL) in anhydrous acetonitrile (1.5 mL) was added EDCI (39 mg, 0.2 mmol) at RT under argon. After the mixture was stirred at RT for 5 min, 5-[1-(4-bromophenyl)-1-methylethyl]-1H-1,2,4-triazol-3-amine (28 mg, 0.1 mmol) was added. The reaction mixture was stirred at RT for 2 h and at 80° C. for 1 h. After the solvents were removed, the residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The aqueous solution was extracted with methylene chloride. The combined organic solutions were dried (Na2SO4), concentrated and purified by silica gel chromatography to give 53 mg (93% yield) of the title compound as a white solid which was used as such for the subsequent step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2CCN(C3C=C(C=CN=3)C(OC)=O)C2=O)=[CH:4][CH:3]=1.[F:25][C:26]1[CH:27]=[C:28]([CH:46]=[CH:47][C:48]=1[F:49])[CH2:29][N:30]1[CH2:34][CH2:33][N:32]([C:35]2[CH:36]=[C:37]([CH:42]=[CH:43][N:44]=2)[C:38](OC)=[O:39])[C:31]1=[O:45].FC1C=CC(CN)=CC=1>>[F:25][C:26]1[CH:27]=[C:28]([CH:46]=[CH:47][C:48]=1[F:49])[CH2:29][N:30]1[CH2:34][CH2:33][N:32]([C:35]2[CH:36]=[C:37]([CH:42]=[CH:43][N:44]=2)[C:38]([NH:7][CH2:6][C:5]2[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=2)=[O:39])[C:31]1=[O:45]
Reactant: COC(=O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Reactant: COC(=O)c1ccnc(N2CCN(Cc3ccc(F)c(F)c3)C2=O)c1
Agent: NCc1ccc(F)cc1
Product: O=C(NCc1ccc(F)cc1)c1ccnc(N2CCN(Cc3ccc(F)c(F)c3)C2=O)c1
Yield: 40 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace methyl 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinate with methyl 2-(3-(3,4-difluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinate to react with 4-fluorobenzylamine, 2-(3-(3,4-difluorobenzyl)-2-oxoimidazolidin-1-yl)-N-(4-fluorobenzyl)isonicotinamide was obtained as a colorless solid in 40% yield: mp 165-167° C.; 1H NMR (300 MHz, CDCl3) δ 8.62 (s, 1H), 8.37 (dd, J=5.1, 0.6 Hz, 1H), 7.41 (dd, J=5.4, 1.5 Hz, 1H), 7.37-7.26 (m, 2H), 7.13-6.97 (m, 5H), 6.80 (br s, 1H), 4.57 (d, J=5.7 Hz, 2H), 4.39 (s, 2H), 4.05 (t, J=8.1 Hz, 2H), 3.38 (t, J=8.1 Hz, 2H); MS (ES+) m/z 441.1 (M+1).
Reaction SMILES: CN1CCOCC1.C(OC(Cl)=O)C(C)C.[C:16]([NH:26][C:27]([CH3:32])([C:29]([OH:31])=O)[CH3:28])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].Cl.[CH3:34][NH:35][O:36][CH3:37].Cl>C(Cl)Cl>[CH3:37][O:36][N:35]([CH3:34])[C:29](=[O:31])[C:27]([NH:26][C:16](=[O:17])[O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([CH3:28])[CH3:32]
Reactant: CNOC
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)C(C)(C)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
N-Methylmorpholine (682 mg, 741 μL, 6.74 mmol) and isobutylchloroformate (460 mg, 441 μL, 3.37 mmol) were added successively to a stirred solution of N-carbobenzyloxy-2-methylalanine (0.64 g, 2.69 mmol) in dry CH2Cl2 at 0° C. under N2. The resulting cloudy mixture was stirred at 0° C. for 90 min. N,O-Dimethylhydroxylamine hydrochloride (316 mg, 3.24 mmol) was added portionwise and the mixture was warmed to room temperature and stirred for 3 h. The mixture was poured into 1N HCl (30 mL) and extracted with CH2Cl2 (3×40 mL). The combined extracts were washed with 1N HCl (30 mL), dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 40×160 mm, 0-80% EtOAc in hexanes gradient) to afford benzyl {2-[methoxy(methyl)amino]-1,1-dimethyl-2-oxoethyl}carbamate. Rf=0.47 (50% EtOAc in hexanes). LCMS calc.=303.1; found=303.2 (M+Na)+. 1H NMR (500 MHz, CDCl3) δ 7.37-7.29 (m, 5H), 5.82 (s, 1H), 5.09 (s, 2H), 3.60 (s, 3H), 3.18 (s, 3H), 1.60 (s, 6H).
Reaction SMILES: [C:1]([Si:5]([O:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11]I)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[Cu](C#N)C#N.C[Li].[CH2:30]([O:37][C:38]1[CH:39]=[C:40]([CH:56]=[CH:57][CH:58]=1)[CH2:41][C:42]1[C:43](=[O:55])[CH2:44][C@@H:45]([O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])[CH:46]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CCOCC>[CH2:30]([O:37][C:38]1[CH:39]=[C:40]([CH:56]=[CH:57][CH:58]=1)[CH2:41][C@@H:42]1[C@@H:46]([CH2:11][CH2:10][C@@H:9]([O:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C@H:45]([O:47][Si:48]([C:51]([CH3:52])([CH3:53])[CH3:54])([CH3:49])[CH3:50])[CH2:44][C:43]1=[O:55])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCCCC[C@@H](CCI)O[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C=C(Cc2cccc(OCc3ccccc3)c2)C(=O)C1
Agent: N#C[Cu]C#N
Agent: [Li]C
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CCCCC[C@@H](CC[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)[C@@H]1Cc1cccc(OCc2ccccc2)c1)O[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h

Procedure:
A 25 ml two-necked flask was flame dried and allowed to be cooled. (S)-tert-butyl(1-iodooctan-3-yloxy)dimethylsilane (1.18 g, 3.2 mmol) and 11.8 L ether were added to the reaction flask, followed by dropwise addition of tert-butyl-lithium (3.75 ml, 1.7M in pentane) at −70° C. A homogenous solution of copper cyanide (0.29 g, 3.2 mmol) and methyllithium (1.6 ml, 2M in ether) in 5.8 ml ether was cooled from room temperature to −70° C. and added to the reaction flask while stirring for 30 minutes. Then, a solution of (R)-2-(3-(benzyloxy)benzyl)-4-(tert-butyldimethylsilyloxy)cyclopent-2-enone (0.65 g, 1.6 mmol) in 6.5 ml ether at −70° C. was added to the reaction mixture for 30 minutes. The reaction was quenched with 40 ml saturated ammonium chloride (aq) containing 0.4 ml ammonium hydroxide. The reaction mixture was phase separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. The solid was filtered off. The solvent was evaporated off under vacuum. The crude product was purified by chromatography on silica gel using a mixture of hexane and ethyl acetate as a gradient eluent. Yield of the titled compound was 1.1 g (85%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:15]O.Cl>>[OH:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=C(O)c1cc(O)nc2ccccc12
Reactant: CO
Agent: Cl
Product: COC(=O)c1cc(O)nc2ccccc12

Procedure:
To 2-hydroxyquinoline-4-carboxylic acid (V. 5.52 g) is added a saturated methanol/hydrochloric acid mixture in 50 ml aliquots over 5 days. The methanol/hydrochloric acid is then removed under reduced pressure and the residue is carefully treated with aqueous sodium bicarbonate. When the aqueous layer tests basic, the solid is collected, washed with water, and dried under reduced pressure to give methyl 2-hydroxyquinoline-4-carboxylate (VI), mp 240°-241°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[CH:6]=O.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1.CCOCC>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[CH:6]=[N:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1
Reactant: COc1ccc(N)cc1
Reactant: COc1cc(C=O)ccc1O
Solvent: CO
Solvent: CCOCC
Product: COc1ccc(N=Cc2ccc(O)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methoxy-4-hydroxybenzaldehyde (vanillin, 1 g, 6.57 mmol) was dissolved in methanol (30 ml). To this solution was added p-anisidine (0.810 g, 6.57 mmol) and the resultant reaction solution was stirred overnight under nitrogen at room temperature. The reaction solution was taken to dryness in vacuo with the application of heat. The resultant solid was azeotropically mixed with methanol (2×), ether (1×), and again with methanol (2×) to yield yellow crystals. The crystals were triturated with hot ether to yield the title product: 1H NMR (300 MHz, CDCl3); δ 8.36 (S, 1H) 7.60 (S, 1H), 7.30-7.17 (m, 3H), 7.05-6,91 (m, 3H), 6.10 (S, 1H), 3.97 (S, 3H), 3.83 (S, 3H)
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:10]2[N:11]=[C:12]([C:19]([F:22])([F:21])[F:20])[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[N:9]2[N:8]=1)(=O)=O.[C:32]([O:36][C:37]([NH:39][C:40]1([C:44]2[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=2)[CH2:43][CH2:42][CH2:41]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].C(=O)([O-])[O-].[Cs+].[Cs+].CCCCCC>CN(C=O)C>[C:24]1([C:23]2[C:7]([C:47]3[CH:48]=[CH:49][C:44]([C:40]4([NH:39][C:37](=[O:38])[O:36][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:43][CH2:42][CH2:41]4)=[CH:45][CH:46]=3)=[N:8][N:9]3[C:14]([C:15]([F:16])([F:17])[F:18])=[CH:13][C:12]([C:19]([F:20])([F:21])[F:22])=[N:11][C:10]=23)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B(O)O)cc2)CCC1
Reactant: O=S(=O)(Oc1nn2c(C(F)(F)F)cc(C(F)(F)F)nc2c1-c1ccccc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nn4c(C(F)(F)F)cc(C(F)(F)F)nc4c3-c3ccccc3)cc2)CCC1
Temperature: 110 °C
Yield: 55 %

Procedure:
3-Phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-2-yl trifluoromethanesulfonate (230 mg, 0.46 mmol, 1 eq), (4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}-phenyl)boronic acid [Int-2A] (210 mg, 0.68 mmol, 85% purity, 1.5 eq), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (40.8 mg, 0.05 mmol, 0.11 eq) and cesium carbonate (371 mg, 1.14 mmol, 2.5 eq) were dissolved in 3.8 mL DMF and heated under microwave irradiation to a temperature of 110° C. After a hold time of 35 sec the reaction mixture was cooled to it and the volatile components were removed in vacuo. The resulting crude material was purified by preparative MPLC [Biotage Isolera: SNAP cartridge 25 g, hexane→hexane/ethyl acetate (2/1)] to yield a sample of insufficient purity. This was forwarded to another preparative MPLC with adapted gradient [Biotage Isolera: SNAP cartridge 25 g, hexane→hexane/ethyl acetate (4/1)] to give 160 mg (55%) of title compound in 90% purity (UPLC, area-%).