Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:16][O:15][C:14]2[C:5](=[CH:6][C:7]3[C:8]([C:21]([F:24])([F:23])[F:22])=[CH:9][C:10]([O:17][CH:18]([CH3:20])[CH3:19])=[N:11][C:12]=3[CH:13]=2)[N:4]1[CH2:25][C:26]([F:29])([F:28])[F:27].[H-].[Na+].I[CH2:33][CH3:34]>C1COCC1>[CH2:33]([O:1][CH2:2][CH:3]1[CH2:16][O:15][C:14]2[C:5](=[CH:6][C:7]3[C:8]([C:21]([F:22])([F:23])[F:24])=[CH:9][C:10]([O:17][CH:18]([CH3:20])[CH3:19])=[N:11][C:12]=3[CH:13]=2)[N:4]1[CH2:25][C:26]([F:28])([F:29])[F:27])[CH3:34]
Reactant: CCI
Reactant: CC(C)Oc1cc(C(F)(F)F)c2cc3c(cc2n1)OCC(CO)N3CC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCC1COc2cc3nc(OC(C)C)cc(C(F)(F)F)c3cc2N1CC(F)(F)F
Yield: 90.3 %

Procedure:
This compound was prepared according to General Method 16 (EXAMPLE 30) from (±)-2,3-dihydro-2-(hydroxymethyl)-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline (EXAMPLE 28) (10 mg, 0.024 mmol), NaH (4.7 mg, 0.12 mmol) and iodoethane (17 mg, 0.12 mmol) in 1.0 mL THF to afford 9.8 mg (89%) of (±)-2-(ethoxymethyl)-2,3-dihydro-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline, a yellow oil, after flash chromatography (5:1 hexanes:EtOAc). Data for (±)-2-(ethoxymethyl)-2,3-dihydro-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline: Rf 0.60 (5:1 hexanes: EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.29 (s, 1H), 7.14 (broad s, 1H), 7.00 (s, 1H), 5.48 (hept, 1H, J=6.2), 4.45 (dd, 1H, J=10.9, 1.5), 4.16 (dd, J=10.9, 2.5), 4.00-4.20 (m, 2H), 3.70 (broad t, 1H, J=6.8), 3.54-3.63 (m, 2H), 3.50 (q, 2H, J=6.9), 1.38 (d, 6H, J=6.2), 1.20 (t, 3H, J=7.0).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[Cl:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[C:33]([Cl:35])[CH:34]=1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([C:31]2[CH:30]=[C:29]([Cl:28])[CH:34]=[C:33]([Cl:35])[CH:32]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(-c2cc(Cl)cc(Cl)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), (3,5-dichlorophenyl)boronic acid (1.0 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in methylene chloride (15 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.49 g, 35%).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:10]=1)=[O:5].[CH3:20][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[CH3:18][Si:15]([CH3:16])([CH3:17])[CH2:14][CH2:13][O:12][CH2:11][N:9]1[CH:10]=[C:6]([C:4](=[O:5])[CH3:20])[CH:7]=[N:8]1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1cnn(COCC[Si](C)(C)C)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1cnn(COCC[Si](C)(C)C)c1
Temperature: 25 °C
Yield: 32.8 %

Procedure:
N-Methoxy-N-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide (325.8 mg, 1.14 mmol) in tetrahydrofuran (2 mL) was mixed with methylmagnesium bromide (0.98 M in tetrahydrofuran, 4.32 mL, 4.23 mmol) under cooling with ice and the reaction mixture was warmed slowly to room temperature for 16 hours with stirring. After completion of the reaction, the reaction solution was mixed with saturated aqueous ammonium chloride, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1, to ethyl acetate/MeOH=20/1) to give the desired product (89.9 mg, 33% yield).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([C:9]#[N:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2].[OH-:17].[Na+]>C(O)C>[CH2:1]([C:3]1[C:8]([C:9]([NH2:10])=[O:17])=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2]
Reactant: CCc1c(C#N)cccc1-c1ccccc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CCc1c(C(N)=O)cccc1-c1ccccc1

Procedure:
Under a dry nitrogen atmosphere a mixture of 3-chloro-2-ethyl-[1,1'-biphenyl] (2.3 g, 0.0106 mole), copper cyanide (1.4 g, 0.0016 mole) and pyridine (1.2 g, 0.016 mole) was heated at 195° for approximately 18 hours. The reaction mixture was cooled to room temperature to give a solid. The solid was dissolved in 300 ml of methylene chloride and washed with 25% aqueous ammonium hydroxide and the aqueous phase extracted with 250 ml of methylene chloride. The organic phases were combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated to give 2-ethyl-[1,1'-biphenyl]-3-carbonitrile as a solid. A mixture of ethyl-[1,1'-biphenyl]-3-carbonitrile (2.2 g, 0.0106 mole), 40 ml of 10 N aqueous sodium hydroxide, and 40 ml of ethanol was heated at reflux for approximately 18 hours. The reaction mixture was cooled and the ethanol evaporated under reduced pressure. The remaining aqueous portion was diluted with 100 ml of water, then extracted with three 150 ml portions of methylene chloride. The organic phases were combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated to give 2-ethyl-[1,1'-biphenyl]-3-carboxamide (2.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[O:15][C:14](=O)[NH:13][C:12](=[O:18])[C:11]=3[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[NH4+:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[NH:20][C:14](=[O:15])[NH:13][C:12](=[O:18])[C:11]=3[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(=O)c2c(o1)C(c1ccc(Cl)cc1)CC2
Reactant: [NH4+]
Agent: [OH-]
Product: O=c1[nH]c2c(c(=O)[nH]1)CCC2c1ccc(Cl)cc1
Yield: 91.1 %

Procedure:
A solution of 7-(4-chlorophenyl)-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione (5.4 g, 20.48 mmol) in concentrated ammonium hydroxide (59.8 mL, 1536 mmol) was stirred at 100° C. in a high-pressure vessel for 6 h. The formation of white precipitate was observed during the heating. The solvent was removed in vacuum to provide 7-(4-chlorophenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione (4.9 g, 18.65 mmol, 91% yield) as a off-white solid. LC-MS (M+H)+=263.2. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.37 (2H, d, J=8.2 Hz), 7.19 (1H, d, J=8.5 Hz), 4.16 (1H, d, J=5.2 Hz), 3.79 (1H, br s), 3.17 (1H, s), 2.51 (2H, d, J=1.8 Hz), 1.75-1.85 (1H, m).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH2:21][CH:22]=[O:23])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[CH2:25][CH2:26][NH2:27]>C1C=CC=CC=1>[Si:1]([O:18][CH2:19][CH2:20][CH2:21][CH:22]1[NH:27][CH2:26][CH2:25][O:23]1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OCCCC=O)(c1ccccc1)c1ccccc1
Reactant: NCCO
Solvent: c1ccccc1
Product: CC(C)(C)[Si](OCCCC1NCCO1)(c1ccccc1)c1ccccc1
Reaction time: 1.5 h

Procedure:
A mixture of the 4-(tert-butyldiphenylsilyloxy)butanal (235 mg, 0.72 mmol) in benzene (3 ml) was added dropwise to a solution of hydroxy ethylamine (44 μL, 0.72 mmol) in benzene (3 mL). Powdered molecular sieves (4 Å, 600 mg) were added and the mixture was stirred for 1.5 h, before being filtered through a 20 μm Millipore syringe filter and concentrated. This gave 12 which was used directly and immediately in the synthesis of 13 (infra): 1H NMR(C6D6); δ1.18 (s, 9H), 1.65-1.82 (m, 2H), 2.62 (m, 2H), 3.33 (dd, 3H, J=6.1, 7.5 Hz), 3.69 (t, 3H, J=6.1 Hz), 4.26 (t, 1H), 7.23 (dd, 6H, J=1.9, 3.1 Hz), 7.79 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19](OS(C)(=O)=O)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].N1C=CC=N1>CN(C=O)C.O>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([N:4]2[CH:3]=[C:2]([Br:1])[CH:6]=[N:5]2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Brc1cn[nH]c1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Agent: c1cn[nH]c1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(Br)cn2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 4-bromo-pyrazole (10.44 g, 71.03 mmol) in anhydrous DMF (96 mL), cooled to 0° C., was slowly added NaH (60% in mineral oil) (3.13 g, 78.133 mmol). The solution was stirred for 1 hour at 0° C. 4-Methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (19.82 g, 71.03 mmol) was added slowly and the reaction was heated to 100° C. overnight or until consumption of the pyrazole by NMR. The reaction was cooled to room temperature and water added (20 mL) followed by extraction with EtOAc. The combined extracts were washed with saturated aqueous NaCl (4×20 mL), dried with Na2SO4 and concentrated to afford 4-(4-bromo-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester as an orange oil. The oil was purified using silica gel chromatography eluting with 10% EtOAc/hexanes to 25% EtOAc/hexanes to provide 4-(4-bromo-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (10.55 g, 45% yield) with a Rf=0.4 (25% EtOAc/hexanes, using iodine as the stain). 1H NMR (CDCl3, 400 MHz) δ 7.46 (s, 1H), 7.43 (s, 1H), 4.23 (m, 3H), 2.88 (m, 2H), 2.10 (m, 2H), 1.88 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([OH:25])[C:19]=3[CH:18]=[N:17]2)[CH:5]=[CH:6][C:7]=1[O:8]CC1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([N:16]2[C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([OH:25])[C:19]=3[CH:18]=[N:17]2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: Oc1cccc2c1cnn2-c1ccc(OCc2ccccc2)c(F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Oc1ccc(-n2ncc3c(O)cccc32)cc1F
Yield: 85.2 %

Procedure:
A solution of 1-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}-1H-indazol-4-ol (D39) (3.79 g, 11.3 mmol) in ethyl acetate (150 mL) was hydrogenated overnight at room temperature and pressure over 10% palladium on charcoal (700 mg). The mixture was filtered through a pad of celite, washed with ethyl acetate and the resulting filtrate was concentrated in vacuo. The product was purified by silica gel chromatography eluting with 5-80% ethyl acetate in hexane. The product was then triturated with hexane and the product collected by filtration and dried in a vacuum oven to yield the title compound (Ela) (2.35 g).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[O:7][CH:8]=[C:9]([C:11]([O:13]C)=O)[N:10]=2)[CH2:3]1.[Si:15]([O:32][CH:33]1[CH2:36][NH:35][CH2:34]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C[Al](C)C.C(O)(=O)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Si:15]([O:32][CH:33]1[CH2:34][N:35]([C:11]([C:9]2[N:10]=[C:6]([N:4]3[CH2:3][CH:2]([OH:1])[CH2:5]3)[O:7][CH:8]=2)=[O:13])[CH2:36]1)([C:28]([CH3:31])([CH3:29])[CH3:30])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1coc(N2CC(O)C2)n1
Reactant: CC(C)(C)[Si](OC1CNC1)(c1ccccc1)c1ccccc1
Agent: C[Al](C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(C)(C)[Si](OC1CN(C(=O)c2coc(N3CC(O)C3)n2)C1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
To a solution of 3-hydroxy-1-(4-methoxycarbonyl-1,3-oxazol-2-yl)azetidine (500 mg, 2.52 mmol) (obtained as described in Reference Example 70(7)) in toluene (25 ml) was added a solution of 0.67 M 3-t-butyldiphenylsilyloxyazetidine (obtained as described in Reference Example 42(2))-trimethylaluminium in toluene (11.3 ml) at room temperature under an atmosphere of nitrogen and the mixture was stirred in an oil bath (80° C.) for 15 minutes. After checking the completion of the reaction, to the reaction mixture were added 10% aqueous acetic acid (20 ml) and ethyl acetate (50 ml) in an ice bath and the mixture was stirred at room temperature for 0.5 hours. To the reaction mixture was added ethyl acetate. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using methylene chloride:methanol (95:5→9:1) as the eluant to afford 1-[4-(3-t-butyldiphenylsilyloxyazetidine-1-carbonyl)-1,3-oxazol-2-yl]-3-hydroxyazetidine (1.24 g, yield 100%) as a pale brown solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH:23]1([C:26](Cl)=[O:27])[CH2:25][CH2:24]1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[O:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:9]([N:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=1)[C:26]([CH:23]1[CH2:25][CH2:24]1)=[O:27])=[O:10]
Reactant: O=C(Nc1cccc(I)c1)c1ccco1
Reactant: O=C(Cl)C1CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccco1)N(C(=O)C1CC1)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 40.2 %

Procedure:
3.19 g of furan-2-carboxylic acid (3-iodo-phenyl)-amide (Example 13bf)) are dissolved in 25 ml of methylene chloride with 2.78 ml of triethylamine and 100 mg of 4-dimethylaminopyridine. 1.60 g of cyclopropanecarbonyl chloride are added thereto and the mixture is stirred at room temperature for 5 hrs. The mixture is concentrated, poured into water and extracted three times with ethyl acetate. Chromatography on silica gel with ethyl acetate/hexane 3:7 gives 1.56 g of cyclopropanecarboxylic acid (furan-2-carbonyl)-(3-iodo-phenyl)-amide as a colourless solid. Yield: 58%. Mass spectrum: peaks inter alia at m/e: 381 (20%), 353 (28%), 313 (86%), 95 (75%), 69 (100%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:14]2[CH:15]=[C:16]([O:19][CH2:20][C@@H:21]([NH:26]C(=O)OC(C)(C)C)[CH2:22][CH:23]([CH3:25])[CH3:24])[CH:17]=[CH:18][C:13]=2[C:12]2[C:7](=[CH:8][N:9]=[CH:10][CH:11]=2)[C:6]1=[O:34].Cl.O1CCOCC1>CO>[NH2:26][C@@H:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:20][O:19][C:16]1[CH:17]=[CH:18][C:13]2[C:12]3[C:7](=[CH:8][N:9]=[CH:10][CH:11]=3)[C:6](=[O:34])[N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:14]=2[CH:15]=1
Reactant: COCCn1c(=O)c2cnccc2c2ccc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)cc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COCCn1c(=O)c2cnccc2c2ccc(OC[C@@H](N)CC(C)C)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.8 %

Procedure:
To a solution of (S)-tert-butyl (1-((6-(2-methoxyethyl)-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (0.080 g, 0.170 mmol) in anhydrous methanol (5 mL) was added a 4M solution of HCl in 1,4-dioxane (0.21 mL, 0.85 mmol) dropwise at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure to afford crude compound which was purified by preparative HPLC (10 mM ammonium acetate in water:acetonitrile) to afford (S)-8-((2-amino-4-methylpentyl)oxy)-6-(2-methoxyethyl)benzo[c][2,7]naphthyridin-5(6H)-one (20 mg, 0.054 mmol, 32% yield) a white solid. LC/MS (ESI) m/e 370.2 [(M+H)+, calcd for C21H28N3O3 370.2]; LC/MS retention time (method A): tR=1.34 min; HPLC retention time (method A): tR=8.36 min; HPLC retention time (method B): tR=8.78 min. 1H NMR (400 MHz, CD3OD) δ ppm 9.45 (s, 1H), 8.76 (d, J=5.77 Hz, 1H), 8.40 (d, J=9.03 Hz, 1H,), 8.23 (d, J=6.02 Hz, 1H), 7.29 (d, J=2.26 Hz, 1H), 7.11 (d, J=8.78 Hz, 1H), 4.61 (t, J=5.65 Hz, 2H), 4.36 (s, 1H), 4.20 (s, 1H), 3.81 (t, J=5.77 Hz, 2H), 3.63-3.71 (m, 1H), 3.37 (s, 3H), 1.86 (m, 1H), 1.67 (qt, J=14.01, 7.09 Hz, 2H), 1.06 (d, J=5.77 Hz, 6H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[Cl:11][CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16]>>[Cl:11][CH2:12][CH2:13][CH2:14][C:15]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)=[O:16]
Reactant: O=C(Cl)CCCCl
Reactant: c1ccc2c(c1)CCNC2
Product: O=C(CCCCl)N1CCc2ccccc2C1

Procedure:
from 3,4-dihydro-1H-isoquinoline and 4-chlorobutanoyl chloride
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:23][CH2:22][C:8]2([CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][C:15]([F:21])([C:18](O)=[O:19])[CH2:14][CH2:13]3)[CH2:9]2)[CH2:7]1)=[O:5])[CH3:2].Cl.[CH3:25][C:26]1([NH2:30])[CH2:29][CH2:28][CH2:27]1.CCN(C(C)C)C(C)C>S(Cl)(Cl)=O>[F:21][C:15]1([C:18](=[O:19])[NH:30][C:26]2([CH3:25])[CH2:29][CH2:28][CH2:27]2)[CH2:16][CH2:17][N:12]([CH:10]2[CH2:11][C:8]3([CH2:22][CH2:23][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7]3)[CH2:9]2)[CH2:13][CH2:14]1
Reactant: CC1(N)CCC1
Reactant: CCOC(=O)N1CCC2(CC(N3CCC(F)(C(=O)O)CC3)C2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: CCOC(=O)N1CCC2(CC(N3CCC(F)(C(=O)NC4(C)CCC4)CC3)C2)C1
Temperature: 90 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
Crude 1-[6-(ethoxycarbonyl)-6-azaspiro[3.4]oct-2-yl]-4-fluoropiperidine-4-carboxylic acid was suspended in thionyl chloride (3 mL) and the reaction was stirred at 90° C. for 2 h. The reaction mixture was cooled to rt and concentrated in vacuo. The residue was dissolved in DCM (5 mL) and (1-methylcyclobutyl)amine hydrochloride (0.196 g, 1.62 mmol) and DIPEA (0.523 g, 0.71 mL, 4.05 mmol) were added, the reaction mixture was stirred overnight at rt. The reaction mixture was partitioned between DCM and sat. NaHCO3 sol., organic layer washed with sat. NaCl sol. and dried over MgSO4. The residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 μm, 60 A, 12 mL per min, gradient 0% to 6% MeOH in DCM]) to give ethyl 2-{4-fluoro-4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate (0.09 g, 28%) as a pale yellow gum as a mixture of diastereomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[CH3:24][NH:25][CH2:26][CH2:27][CH2:28][C:29]1[CH:39]=[CH:38][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][CH:30]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:25]([CH2:26][CH2:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:38][CH:39]=2)[CH3:24])=[O:23])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: CCOC(=O)c1ccc(CCCNC)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(CCCN(C)C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Reaction time: 8 h
Yield: 67 %

Procedure:
To a stirred solution of 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (456 mg, 1.45 mmol) and ethyl 4-(3-methylamino-1-propyl)benzoate (220 mg, 1.45 mmol) were added EDC.HCl (417 mg, 2.16 mmol), HOBt (cat.), and DMAP (catalytic amount) in DMF (10 mL), and the resulting mixture was stirred overnight. The mixture was diluted with EtOAc (300 mL), washed with brine, dried over MgSO4, and evaporated. The residue was chromatographed on silica-gel with CHCl3-EtOH (10:1) to give 503 mg (71%) ethyl 4-[3-[3-methoxy-4-[N′-(2-methylphenyl) ureido]phenylacetyl-N-methylamino]-1-propyl]benzoate as a yellow oil. MS (FAB) m/z 518(M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]3=[N:12][C:13](Cl)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:36]([O:39][C:40]([CH3:60])([CH3:59])[C:41](=[O:58])[NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45](B2OC(C)(C)C(C)(C)O2)[CH:44]=1)(=[O:38])[CH3:37].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[C:36]([O:39][C:40]([CH3:60])([CH3:59])[C:41]([NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([C:13]2[N:12]=[C:11]3[N:17]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5([NH:28][C:29]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:35])[CH2:27][CH2:26][CH2:25]5)=[CH:20][CH:19]=4)[C:8]([C:7]4[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=4)=[N:9][C:10]3=[CH:15][CH:14]=2)[CH:44]=1)=[O:58])(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)(C)C(=O)Nc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(Cl)nc43)cc2)CCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)OC(C)(C)C(=O)Nc1cccc(-c2ccc3nc(-c4cccnc4N)n(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c3n2)c1
Temperature: 80 °C
Yield: 63.9 %

Procedure:
To a suspension of tert-butyl (1-{4-[2-(2-aminopyridin-3-yl)-5-chloro-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}cyclobutyl)carbamate (50 mg) and 1,1-dimethyl-2-oxo-2-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amino}ethyl acetate (71 mg) and potassium phosphate (65 mg) and PdCl2(dppf)CH2Cl2 (8 mg) in dioxane (2 mL) and H2O (0.2 mL) was degassed for 5 minutes and then heated to 80° C. for 18 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (2 times: 0-10% methanol in chloroform then 0-10% methanol in ethyl acetate) gave the product (44 mg, 64%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:2]=1.C([Li])(C)(C)C.N1([CH:26]=[O:27])CCCCC1>C1COCC1.CCCCC>[CH:26]([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][C:3]=1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:27]
Reactant: CC(C)(C)OC(=O)Nc1cccnc1
Reactant: O=CN1CCCCC1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cnccc1C=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 60.3 %

Procedure:
A solution of tert-butyl pyridin-3-ylcarbamate (17.7 g, 91.1 mmol) in THF (300 mL) was cooled to −78° C. and treated with 1.70 M tert-butyllithium in pentane (129 mL). Upon completion of the addition, the reaction was stirred at −78° C. for an additional 15 min and then at −20° C. for 1.5 h. 1-piperidinecarboxaldehyde (30.4 mL, 0.273 mol) was added while the temperature was maintained below at −15° C., and then the mixture was allowed to stir at room temperature overnight. The solution was cooled to 0° C. and was quenched by the addition of 1 M HCl to bring the pH to 2. Solid Na2CO3 was then added to adjust the pH to 7. The solution was extracted with ethyl acetate three times, and the combined organic solutions were washed with water (3×) and brine. The organic layer was dried, filtered, and volatiles evaporated. The residue was purified by silica gel chromatography (50% ethyl acetate/hexanes) to give the desired product as a yellow solid (12.2 g, 60%). LCMS for C11H15N2O3(M+H)+: m/z=223.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[N+:16]([C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22])([O-:18])=[O:17]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:21](=[O:22])[C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[N+:16]([O-:18])=[O:17])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Product: O=C(NC1CCCc2c1[nH]c1ccc(Br)cc21)c1ccccc1[N+](=O)[O-]

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-nitrobenzamide was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and 2-nitrobenzoyl chloride in a similar manner as described above to give an orange solid (39% yield). 1H-NMR (CDCl3): δ 8.73 (s, 1H), 8.08 (m, 1H), 7.68 (m, 1H), 7.60 (m, 2H), 7.54 (m, 1H), 7.29-7.21 (m, 2H), 6.15 (d, 1H), 5.42 (m, 1H), 2.69 (m, 2H), 2.33 (m, 1H), 1.96 (m, 3H); MS m/z 414 (M−1).