Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH:5]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][C:12]([C@H:15]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[CH2:16][C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=3)=[O:18])=[CH:11][CH:10]=2)[CH2:6]1.C(N(CC)C(C)C)(C)C>ClCCl>[C:1]([N:5]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][C:12]([C@H:15]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[CH2:16][C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=3)=[O:18])=[CH:11][CH:10]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(C3CNC3)cc2)c2ccccc2C)ccn1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CC(c2ccc([C@@H](CC(=O)c3ccnc(C)c3)c3ccccc3C)cc2)C1
Yield: 24.4 %

Procedure:
Acetyl chloride (30 mg) was added at room temperature to a solution of (R)-3-(4-(azetidin-3-yl)phenyl)-1-(2-methylpyridin-4-yl)-3-o-tolylpropan-1-one (example 482, step 1; 70 mg) and N,N-diisopropylethylamine (98 mg) in dichloromethane (4 mL), then after 2 h the reaction mixture was partitioned between sat. aq. sodium hydrogencarbonate solution and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated. Flash chromatography (silica gel, 10 g, 2% to 5% methanol in dichlormethane) produced the title compound (19 mg). Colourless oil, MS (ESI+): m/z=413.0 [M+H]+.
Reaction SMILES: [BH4-].[Na+].O[N:4]=[C:5]([C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([O:40][CH3:41])[CH:38]=2)[N:33]=[CH:32][C:31]=1[F:42])[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[CH2:10][CH:9]1[CH2:25][C:26]([O:28][CH3:29])=[O:27]>CO.[Mo](=O)(=O)=O>[NH2:4][CH:5]([C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([O:40][CH3:41])[CH:38]=2)[N:33]=[CH:32][C:31]=1[F:42])[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[CH2:10][CH:9]1[CH2:25][C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)CC1CN(CCSc2cc(F)ccc2F)CCC1CCC(=NO)c1c(F)cnc2ccc(OC)cc12
Agent: O=[Mo](=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC1CN(CCSc2cc(F)ccc2F)CCC1CCC(N)c1c(F)cnc2ccc(OC)cc12
Temperature: -2 °C
Yield: 51.8 %

Procedure:
0.261 g of sodium borohydride was added, in several portions, to a mixture of 0.4 g of methyl (3RS,4RS)-4-[3-hydroxyimino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-acetate in 25-cm3 of methanol cooled in the region of −2° C., with stirring and under an inert atmosphere. The reaction mixture was stirred in the region of 0° C. for 20 minutes and then 0.14 g of molybdenum trioxide were added. The reaction mixture was stirred in the region of 20° C. for 24 hours and then it was cooled in the vicinity of −2° C. and 0.261 g of sodium borohydride and 0.14 g of molybdenum trioxide were again added. The reaction mixture was stirred for 18 hours in the region of 20° C. and then filtered on celite. The filtrate was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The evaporation residue was purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3 cm), eluting with a successive mixture of cyclohexane-ethyl acetate (50/50 by volume) and then dichloromethane-methanol (90/10 by volume) and collecting 10-cm3 fractions. Fractions 26 to 41 were combined and then concentrated to dryness according to the conditions described above. 0.202 g of methyl (3RS,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-acetate were obtained in the form of a colorless oil.
Reaction SMILES: C([N:8]1[CH2:25][C:12]2([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[O:11][CH:10]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[OH-].[OH-].[Pd+2]>[C:26]1([CH:10]2[CH2:9][NH:8][CH2:25][C:12]3([CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:16][CH2:17]3)[O:11]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(Cc1ccccc1)CC(c1ccccc1)O2
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CNCC(c1ccccc1)O2
Temperature: 60 °C
Yield: 92.5 %

Procedure:
To tert-butyl 10-benzyl-8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecane-3-carboxylate (1.58 g, 3.74 mmol) and Pd(OH)2 (280 mg, 0.40 mmol) in ethanol (16 mL) was added ammonium formate (1.10 g, 17.39 mmol) and the reaction mixture was heated to 60° C. for 40 min. The reaction mixture was cooled, filtered, concentrated to 10% of original volume, diluted with ethyl acetate and washed with sat. aq. NaHCO3 (pH 10)/brine. The aqueous was extracted further with ethyl acetate and the combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give tert-butyl 8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecane-3-carboxylate (1.15 g, 93%) as a white solid. ESI-MS m/z calc. 332.2. found 333.3 (M+1)+; Retention time: 1.13 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.40-7.23 (m, 5H), 4.69 (dd, J=10.7, 2.7 Hz, 1H), 3.76 (br. s, 2H), 3.31 (t, J=10.7 Hz, 1H), 3.17-3.02 (m, 2H), 2.75 (dd, J=35.5, 12.4 Hz, 2H), 2.63 (dd, J=12.3, 10.8 Hz, 1H), 2.49 (d, J=12.5 Hz, 1H), 1.69-1.57 (m, J=12.6 Hz, 1H), 1.57-1.39 (m, 11H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][O:8][C:9]2[C:10]([F:19])=[C:11]([C:15]([F:18])=[CH:16][CH:17]=2)[C:12]([NH2:14])=[O:13])=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1.C([Sn](CCCC)(CCCC)[C:33]1[S:34][CH:35]=[CH:36][N:37]=1)CCC.O>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:19][C:10]1[C:9]([O:8][CH2:7][C:5]2[S:6][C:2]([C:33]3[S:34][CH:35]=[CH:36][N:37]=3)=[C:3]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:4]=2)=[CH:17][CH:16]=[C:15]([F:18])[C:11]=1[C:12]([NH2:14])=[O:13]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: COc1ccc(-c2nc(COc3ccc(F)c(C(N)=O)c3F)sc2Br)cc1
Agent: [Pd]
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(COc3ccc(F)c(C(N)=O)c3F)sc2-c2nccs2)cc1
Temperature: 120 °C
Yield: 3.3 %

Procedure:
To a solution of 3-[5-bromo-4-(4-methoxy-phenyl)-thiazol-2-ylmethoxy]-2,6-difluoro-benzamide (0.1 g, 0.2 mmol) in 5 ml of anhydrous DMF was added 2-tributylstannyl thiazole (0.071 g, 0.2 mmol) and degassed the reaction mixture for the 10 minutes. Then added tetraphenylphosphine palladium (0) (0.026 g, 0.2 mmol). The reaction mixture was heated at 120° C. for 12 h under the nitrogen atmosphere. Then reaction mixture was cooled to rt. 100 ml of water was added into it and extracted the compound with ethyl acetate, The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The compound was purified by column chromatography on silica (230-400μ) using ethyl acetate (40:60) as the eluent to provide the title compound as yellow solid (0.003 g, 3%). 1H NMR (DMSO-d6, 400 MHz): δ 3.82 (s, 3H), 5.57 (s, 2H), 7.06 (d, 1H, J=8.4 Hz (o-coupling), 7.13 (dt, 1H), 7.39-7.47 (m, 1H), 7.51 (d, 2H, J=8.4 Hz (o-coupling), 7.52-7.58 (m, 1H), 7.59-7.86 (m, 2H), 7.68 (d, 1 H, J=3.2 Hz), 7.84 (d, 1 H, J=3.2 Hz), 7.89 (broad s, 1H), 8.18 (broad s, 1H), 9.12 (s, 1H); MS ES+ (460.01), HPLC (method 5) Rt=15.64 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:11]=2[C:12]([O:27]C(C2C=CC=CC=2)C2C=CC=CC=2)=[C:13]2[C:17](=[O:18])[N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:15][C:14]=12)=[O:4].C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>ClCCl>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][CH:9]=[N:10][C:11]=2[C:12]([OH:27])=[C:13]2[C:17](=[O:18])[N:16]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[CH2:15][C:14]=12)=[O:4]
Reactant: COC(=O)c1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Reaction time: 1 h
Yield: 96.9 %

Procedure:
To a solution of 9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylic acid methyl ester 212 (3 mg, 0056 mmol) in dichloromethane (1 mL) were added TFA (0.1 mL) and triethylsilane (0.2 mL). Stirring was continued at the room temperature for 1 hour and the volatiles were evaporated in vacuo. The residue was triturated in Et2O/hexane to afford 7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylic acid methyl ester 316 (2.0 mg, 100%) as a yellow solid: 1H NMR (CDCl3) δ 9.5 (d, 1H), 9.0 (m, 1H), 7.66 (dd, 1H), 7.35 (dd, 2H), 7.0 (t, 2H), 4.8 (s, 2H), 4.7 (s, 2H), 4.0 (s, 3H); MS: 365 (M−1).
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[C:30]#[N:31])=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[Si](OC(C1OC([Sn](CCCC)(CCCC)CCCC)=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.BrC1C=C(C=CC=1)C#N>>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([C:22]2[O:23][C:24]([C:27]3[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=3)[C:30]#[N:31])=[CH:25][N:26]=2)=[O:8])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(-c2cccc(C#N)c2)o1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: N#Cc1cccc(Br)c1
Product: N#Cc1cccc(-c2cnc(C(=O)CCCCCCc3ccccc3)o2)c1
Yield: 72 %

Procedure:
3-(2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)oxazol-5-yl)benzonitrile. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (60 mg, 0.091 mmol) and 3-bromobenzonitrile following General Procedure A. Flash chromatography (2-5% EtOAc/hexanes) yielded the title compound as a clear oil (31 mg, 72%): 1H NMR (CDCl3, 600 MHz) δ 7.91 (s, 1H), 7.84 (d, 1H, J=7.8 Hz), 7.59 (d, 1H, J=7.8 Hz), 7.53 (t, 1H, J=7.8 Hz), 7.36 (s, 1H), 7.27-7.24 (m, 2H), 7.16-7.15 (m, 3H), 4.83 (t, 1H, J=6.0 Hz), 2.58 (t, 2H, J=7.8 Hz), 1.95-1.88 (m, 2H), 1.65-1.59 (m, 2H), 1.36-1.33 (m, 6H), 0.89 (s, 9H), 0.10 (s, 3H), −0.01 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 166.8, 149.8, 143.6, 132.3, 130.7, 130.2, 129.2, 129.1, 128.9, 128.3, 126.5, 124.2, 119.1, 114.2, 69.5, 37.3, 36.8, 32.3, 30.0, 26.6, 26.6, 26.0, 19.1, −4.1, −4.2.
Reaction SMILES: [C:1]([C:3]1C=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19]([O:22][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].OC1C=CC2C(=O)C3C4C=CC(C#N)=NC=4[NH:39]C=3C(C)(C)C=2C=1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19]([O:22][S:23]([C:26]([F:29])([F:27])[F:28])(=[O:24])=[O:25])=[CH:18][C:10]=4[C:11]([CH3:16])([CH3:17])[C:12]=3[NH:13][C:14]=2[N:39]=1)#[N:2]
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1nc(C#N)ccc21
Product: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1nc(C#N)ccc21

Procedure:
According to the method used for synthesizing Compound B1, 8-hydroxy-10,10-dimethyl-5-oxo-10,11-dihydro-5H-1,11-diaza-benzo[b]fluorene-2-carbonitrile was subjected to trifluoromethanesulfone esterification to obtain the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(=O)([O-])[O-].[K+].[K+].[F:15][C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[OH:23]>>[F:15][C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[O:23][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCBr
Reactant: Oc1cccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCCOc1cccc(F)c1F

Procedure:
Quantities: 1-bromoheptane (46.6 g, 0.26 mol), potassium carbonate (70 g, 0.5 mol) and compound from Example 37 (31.2 g, 0.24 mol). The experimental procedure was as described in Example 38.
Reaction SMILES: N#N.[CH3:3][O:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.CN(C)CCN(C)C.[Li]CCCC.CN([CH:27]=[O:28])C.[NH4+].[Cl-]>C1COCC1.CCCCCCC>[CH3:3][O:4][CH2:5][C:6]1[S:7][C:8]([CH:27]=[O:28])=[CH:9][CH:10]=1
Reactant: COCc1cccs1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: N#N
Agent: [Cl-]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: COCc1ccc(C=O)s1
Temperature: -70 °C
Reaction time: 1.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-(methoxymethyl)thiophene (1.23 g, 9.58 mmol) in THF (50.0 mL) was treated dropwise at −75° C. with N,N,N′,N′-tetramethyl-ethylendiamin (2.69 ml, 17.7 mmol) followed by n-BuLi (6.5 mL of a 2.7 M solution in heptane, 17.7 mmol). The resulting mixture was stirred for 90 min at −70° C. DMF (4.03 mL, 52.1 mmol) was then added and the resulting mixture was allowed to gently warm-up to rt. The mixture was then poured over sat. aq. NH4Cl (40 mL) and the org. layer was extracted with EA (3×20 mL) and the combined org. layers were dried over MgSO4, filtered and the solvent was removed under reduced pressure. Purification of the residue by FC (gradient from 95:5 hept-EA to 85:15 hept-EA) gave the title compound as an orange oil. LC-MS-conditions 07: tR=0.62 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:20]=[C:19]3[C:15]([CH:16]=[N:17][N:18]3[CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:14][CH:13]=2)=[O:10])=[CH:4][CH:3]=1.Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]3[CH:20]=[C:19]4[C:15]([CH:16]=[N:17][N:18]4[CH2:21][CH2:22][N:23]4[CH2:24][CH2:25][CH2:26][CH2:27]4)=[CH:14][CH:13]=3)=[O:10])=[CH:4][CH:3]=2)=[CH:31][CH:32]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C(Cc1ccc(O)cc1)Nc1ccc2cnn(CCN3CCCC3)c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(OCc2ccc(F)cc2)cc1)Nc1ccc2cnn(CCN3CCCC3)c2c1
Reaction time: 6 h

Procedure:
A mixture of 2-(4-hydroxy-phenyl)-N-[1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-yl]-acetamide (45.0 mg, 0.124 mmol), 1-bromomethyl-4-fluoro-benzene (35.0 mg, 0.185 mmol), Cs2CO3 (60.0 mg, 0.184 mmol) in 2 mL of DMF was shaken for 6 hours and concentrated under reduced pressure. The residue was dissolved in a 1:1 mixture of dimethyl sulfoxide/MeOH (1.5 mL) and purified by preparative reverse-phase HPLC. 1H NMR (500 MHz, DMSO-D6) δ ppm 1.82 (m, 2 H), 1.98 (m, J=7.02, 7.02 Hz, 2 H), 3.02 (m, 2 H), 3.48 (m, 2 H), 3.68 (m, 4 H), 4.65 (t, J=6.24 Hz, 2 H), 5.07 (s, 2 H), 6.97 (m, 2 H), 7.11 (m, 1 H), 7.21 (m, 2 H), 7.27 (m, 2 H), 7.48 (m, 2 H), 7.71 (m, 1 H), 8.08 (s, 1 H), 8.26 (s, 1 H), 10.35 (s, 1 H); MS (ESI) m/z 473 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.CO[C:16]([N:20]([CH3:22])[CH3:21])(OC)[CH3:17]>C(OCC)C>[CH3:21][N:20]([CH3:22])[C:16]([CH3:17])=[CH:10][C:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:13])[F:1])=[CH:8][CH:7]=1)=[O:11]
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: COC(C)(OC)N(C)C
Solvent: CCOCC
Product: CC(=CC(=O)c1ccc(C(F)(F)F)cc1)N(C)C
Temperature: 112 °C

Procedure:
A mixture of 4′-(trifluoromethyl)acetophenone (9.8 g) and N-(1,1-dimethoxyethyl)-N,N-dimethylamine (8.2 g) was heated at 112° C. overnight, under nitrogen. The reaction mixture was cooled and concentrated giving an orange solid. Trituration with diethyl ether gave the title compound as a yellow solid
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].CC(C)([O-])C.[Na+].[Br:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34]I)=[C:29]([Cl:36])[CH:28]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.CN(C)C=O>[Br:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:5]([NH:11][C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])([C:4]([O:3][CH2:1][CH3:2])=[O:19])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:29]([Cl:36])[CH:28]=1
Reactant: CCOC(=O)C(NC(=O)OC(C)(C)C)C(=O)OCC
Reactant: Clc1cc(Br)ccc1CCI
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCc1ccc(Br)cc1Cl)(NC(=O)OC(C)(C)C)C(=O)OCC
Reaction time: 15 h
Yield: 64.7 %

Procedure:
Diethyl(tert-butoxycarbonyl)aminomalonate (202 g) was dissolved in a mixed solution of tetrahydrofuran (6000 mL) and N,N-dimethylformamide (714 mL), and sodium tert-butoxide (70.5 g) was added. After heating the mixture to the refluxing temperature, a solution of 2-(4-bromo-2-chlorophenyl)ethyl iodide (246 g) of Reference Example 18 in tetrahydrofuran (940 mL) was added to the reaction mixture, and the mixture was refluxed with stirring for 15 hr. After cooling, the reaction mixture was poured into 25% aqueous citric acid solution. After partitioning and extraction with ethyl acetate, the organic layer was washed with water and 25% brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (227 g) as a pale-yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:20][CH2:21][O:22][CH3:23])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][C:7]1=[O:19])=[O:5])[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([O:3][C:4]([C:6]1([CH2:20][CH2:21][O:22][CH3:23])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH:7]1[OH:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(CCOC)CCN(Cc2ccccc2)CC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C1(CCOC)CCN(Cc2ccccc2)CC1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.4 %

Procedure:
To a solution of 1-benzyl-4-(2-methoxy-ethyl)-3-oxo-piperidine-4-carboxylic acid ethyl ester (774 mg, 2.42 mmol) in MeOH (5 mL) at 0° C. was carefully added sodium borohydride (110 mg, 2.91 mmol) and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was quenched with 1N NaOH and diluted with further 1N NaOH and ethyl acetate. The organic layer was separated washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give a crude residue which was purified by flash column chromatography to give 1-benzyl-3-hydroxy-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (610 mg, 78%) as a white solid. MS (ESI): 322.3 (MH+).
Reaction SMILES: Br[C:2]1[O:10][C:9]2[CH:8]=[CH:7][NH:6][C:5](=[O:11])[C:4]=2[CH:3]=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([B-]23OCC(C)(CO2)CO3)=[N:17][CH:18]=1.[Li+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cu]I.CC(N(C)C)=O>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:2]2[O:10][C:9]3[CH:8]=[CH:7][NH:6][C:5](=[O:11])[C:4]=3[CH:3]=2)=[N:17][CH:18]=1
Reactant: CC12CO[B-](c3ccc(Cl)cn3)(OC1)OC2
Reactant: O=c1[nH]ccc2oc(Br)cc12
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)N(C)C
Product: O=c1[nH]ccc2oc(-c3ccc(Cl)cn3)cc12
Temperature: 250 °C
Yield: 29.9 %

Procedure:
A mixture of 2-bromofuro[3,2-c]pyridin-4(5H)-one (200 mg), lithium 1-(5-chloropyridin-2-yl)-4-methyl-2,6,7-trioxa-1-borabicyclo[2.2.2]octan-1-uide (462 mg), palladium(II) acetate (21.0 mg), copper(I) iodide (178 mg), triphenylphosphine (49.0 mg) and DMA (1.0 mL) was heated at 250° C. for 30 min under microwave irradiation. The reaction mixture was purified by silica gel column chromatography (NH, methanol/ethyl acetate), and the obtained solid was washed with diisopropyl ether to give the title compound (69.0 mg) as a white solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[O-:6][N+:7]1[C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][C:11]=2[N:10]=[C:9]([CH2:20][CH2:21][CH:22]=O)[N:8]=1)[CH2:17][CH2:16][CH2:15]3.[BH3-]C#N.[Na+].CC(O)=O>CO>[N:1]1([CH2:22][CH2:21][CH2:20][C:9]2[N:8]=[N+:7]([O-:6])[C:12]3[CH:13]=[C:14]4[C:18]([CH2:17][CH2:16][CH2:15]4)=[CH:19][C:11]=3[N:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CCCc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Reactant: C1CCNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: [O-][n+]1nc(CCCN2CCCC2)nc2cc3c(cc21)CCC3
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
Pyrrolidine (3.0 g, 42 mmol) was added to a stirred solution of propanal 75 (1.5 g, 6.2 mmol) in MeOH (100 mL) at 0° C. and the solution stirred for 30 min. NaCNBH3 (1.5 g, 24 mmol) was added and the solution stirred at 0° C. for 30 min and then HOAc (2 mL) was added and the mixture was stirred at 20° C. for 16 h. The solvent was evaporated and the residue was partitioned between DCM (200 mL) and water (200 mL). The aqueous phase was extracted with DCM (2×200 mL), the combined organic phase was dried and the solvent evaporated. The residue was purified by chromatography, eluting with 10% MeOH/EtOAc, to give 1-oxide 84 (1.5 g, 84%) as a yellow oil: 1H NMR [(CD3)2SO] δ 8.25 (s, 1H, H-9), 7.74 (s, 1H, H-5), 3.10-3.16 (m, 4H, H-6, H-8), 3.02-3.09 (m, 2H, CH2N), 2.80-2.88 (m, 6H, 3×CH2), 2.17-2.28 (m, 4H, H-7, CH2), 1.82-1.90 (m, 4H, 2×CH2); 13C NMR δ 165.0, 154.8, 149.2, 147.2, 132.3, 122.7, 114.3, 55.0, 53.4 (2), 34.8, 33.2, 32.8, 25.7, 25.5, 23.4 (2); HRMS calcd for C17H22N4O (M+) m/z 298.1794, found 298.1794.
Reaction SMILES: [C:1]([NH:7][C:8](=[O:30])[NH:9][C:10]1[N:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:29])OC(C)=C)[CH:18]=2)=[CH:12][CH:11]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Cl.Cl.[CH3:33][N:34]([CH3:41])[CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.CN1CCCC1>O1CCOCC1>[CH3:33][N:34]([CH3:41])[CH:35]1[CH2:40][CH2:39][N:38]([C:24]([NH:23][C:19]2[CH:18]=[C:17]([O:16][C:13]3[CH:14]=[N:15][C:10]([NH:9][C:8]([NH:7][C:1](=[O:6])[C:2]([CH3:3])([CH3:5])[CH3:4])=[O:30])=[CH:11][CH:12]=3)[CH:22]=[CH:21][N:20]=2)=[O:29])[CH2:37][CH2:36]1
Reactant: CN(C)C1CCNCC1
Reactant: C=C(C)OC(=O)Nc1cc(Oc2ccc(NC(=O)NC(=O)C(C)(C)C)nc2)ccn1
Agent: CN1CCCC1
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)C1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)C(C)(C)C)nc3)ccn2)CC1
Temperature: 25 °C
Yield: 13 %

Procedure:
A mixture of Example C2 (0.42 g, 1.02 mmol), 4-(dimethylamino)piperidine dihydrochloride (0.204 g, 1.02 mmol) and N-methylpyrrolidine (0.182 g, 2.13 mmol) in dioxane (5 mL) was heated at 80° C. overnight, cooled to RT, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM). The resultant material was dissolved in MeCN/H2O, frozen and lyophilized to afford 4-(dimethylamino)-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)piperidine-1-carboxamide as a yellowish solid (64 mg, 13%). 1H NMR (400 MHz, DMSO-d6): δ 11.17 (s, 1H), 10.40 (s, 1H), 9.23 (s, 1H), 8.18 (d, J=2.9 Hz, 1H), 8.07 (d, J=5.7 Hz, 1H), 8.03 (d, J=9.0 Hz, 1H), 7.66 (dd, J=9.0, 2.9 Hz, 1H), 7.32 (d, J=2.4 Hz, 1H), 6.56 (dd, J=5.7, 2.4 Hz, 1H), 4.13-4.01 (m, 2H), 3.37-3.11 (br s, 1H), 2.74-2.62 (m, 2 H), 2.28 (s, 6H), 1.76-1.70 (m, 2H), 1.29-1.24 (m, 2H), 1.16 (s, 9H); MS (ESI) m/z: 484.3 (M+H+).