Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:9][C:10]1([F:16])[CH2:13][CH:12]([C:14]#[N:15])[CH2:11]1.C1(C)C=CC=CC=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+]>CCOC(C)=O.O>[Cl:8][C:7]1[C:2]([C:12]2([C:14]#[N:15])[CH2:13][C:10]([F:16])([F:9])[CH2:11]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CC1CC(F)(F)C1
Reactant: Clc1cccnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: N#CC1(c2ncccc2Cl)CC(F)(F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
To a 100 mL round bottom flask was added 2,3-dichloropyridine (2.9 g, 20 mmol), 3,3-difluorocyclobutanecarbonitrile (2.1 g, 18 mmol), and toluene (50 mL). The mixture was cooled to ° C. and sodium hexamethyldisilazide (NaHMDS, 2.0 M in THF, 11 mL, 22 mmol) was added. The reaction mixture was warmed to rt and stirred for 2 h. The mixture was then diluted with EtOAc (20 mL) and water (20 mL). The aqueous layer was extracted with EtOAc and the combined organic phases were washed with brine, dried over Na2SO4, and concentrated to provide the desired product (3.4 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5](I)=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)O1.[CH2:24]([OH:27])[CH2:25][OH:26]>>[Cl:1][C:2]1[N:7]=[C:6]([O:26][CH2:25][CH2:24][OH:27])[C:5]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2cccs2)OC1(C)C
Reactant: OCCO
Reactant: Clc1ncc(I)c(Cl)n1
Product: OCCOc1nc(Cl)ncc1-c1cccs1

Procedure:
Preparation according to procedures 4b and 3 with the use of 2,4-dichloro-5-iodopyrimidine, 1,2-ethandiol and 4,4,5,5-tetramethyl-2-(2-thienyl)-1,3,2-dioxaborolane.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:9][N:8]([C:10](=[O:22])[CH:11]([NH:14]C(OC(C)(C)C)=O)[CH2:12][CH3:13])[CH:7]([CH2:23][C:24]2[C:32]3[C:27](=[CH:28][C:29]([F:33])=[CH:30][CH:31]=3)[NH:26][C:25]=2[C:34]2[NH:35][C:36]3[C:41]([C:42]=2[CH2:43][CH:44]2[N:48]([C:49](=[O:61])[CH:50]([NH:53]C(OC(C)(C)C)=O)[CH2:51][CH3:52])[CH2:47][CH:46]([O:62][C:63](=[O:65])[CH3:64])[CH2:45]2)=[CH:40][CH:39]=[C:38]([F:66])[CH:37]=3)[CH2:6]1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([O:4][CH:5]1[CH2:9][N:8]([C:10](=[O:22])[CH:11]([NH2:14])[CH2:12][CH3:13])[CH:7]([CH2:23][C:24]2[C:32]3[C:27](=[CH:28][C:29]([F:33])=[CH:30][CH:31]=3)[NH:26][C:25]=2[C:34]2[NH:35][C:36]3[C:41]([C:42]=2[CH2:43][CH:44]2[N:48]([C:49](=[O:61])[CH:50]([NH2:53])[CH2:51][CH3:52])[CH2:47][CH:46]([O:62][C:63](=[O:65])[CH3:64])[CH2:45]2)=[CH:40][CH:39]=[C:38]([F:66])[CH:37]=3)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCC(NC(=O)OC(C)(C)C)C(=O)N1CC(OC(C)=O)CC1Cc1c(-c2[nH]c3cc(F)ccc3c2CC2CC(OC(C)=O)CN2C(=O)C(CC)NC(=O)OC(C)(C)C)[nH]c2cc(F)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(N)C(=O)N1CC(OC(C)=O)CC1Cc1c(-c2[nH]c3cc(F)ccc3c2CC2CC(OC(C)=O)CN2C(=O)C(N)CC)[nH]c2cc(F)ccc12
Temperature: 0 °C

Procedure:
A solution containing 11 (27.5 g, 30 mmol) in DCM (200 mL) was cooled to 0° C. TFA (50 mL) was added and the reaction was monitored by LC/MS analysis until complete conversion of 11 to 12 (ca. 3 h). The solvent was removed in vacuo and the dark, green-colored residue was dissolved in EtOAc (ca. 1 L). The EtOAc solution was carefully poured into a saturated aqueous NaHCO3/ice/water mixture to neutralize the residual TFA. The organic phase was separated and washed twice with saturated aqueous NaHCO3 then once with brine. The combined aqueous washes were back-extracted with EtOAc (2×100 mL) and the combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to afford 22 g of crude 12 as an off-white solid. 1H NMR (300 MHz, CDCl3+d4-MeOH), mixture of rotomers: δ11.62 (br s, 2H), 7.48-7.62 (m, 4H), 6.89 (ddd, J=2.4, 9.3, 9.3 Hz, 2H), 5.48 (dd, J=4.5, 4.8 Hz, 2H), 4.52 (dd, J=9.3, 9.3 Hz, 2H), 4.06 (dd, J=4.8, 12.3 Hz, 2H), 3.78 (d, J=12.3 Hz, 2H), 3.54-3.70 (m, 4H), 3.30-3.40 (m, 2H), 2.33 (s, 6H), 2.02-2.16 (m, 2H), 1.70-1.96 (m, 4H), 1.09 (t, J=7.2 Hz, 6H) ppm; 13C NMR (75 MHz, CDCl3+d4-MeOH): δ173.5, 170.9, 161.8, 158.6, 137.2, 137.1, 128.2, 128.1, 125.6, 118.7, 118.6, 108.6, 108.3, 108.0, 98.6, 98.1, 74.6, 60.1, 53.5, 33.5, 28.0, 21.4, 9.7 ppm. Mass spectrum (ESI), m/z 721.4 [(M)+; calcd for C38H46F2N6O6: 720.8].
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([OH:14])[C:10]([CH3:23])([CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[H-].[Na+].[C:31](=[S:33])=[S:32].I[CH3:35]>C1COCC1>[C:31]([S:33][CH3:35])(=[S:32])[O:14][C:11]1([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][C:10]1([CH3:23])[CH3:22]
Reactant: S=C=S
Reactant: CC1(C)CN(Cc2ccccc2)CCC1(O)c1ccc(Cl)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CSC(=S)OC1(c2ccc(Cl)cc2)CCN(Cc2ccccc2)CC1(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 83.1 %

Procedure:
A solution of 1-benzyl-4-(4-chlorophenyl)-3,3-dimethylpiperidin-4-ol (6.9 g, 20.92 mmol) and imidazole (0.214 g, 3.14 mmol) in THF (175 mL) was treated with sodium hydride (2.510 g, 62.8 mmol) in two portions. The mixture was heated at reflux overnight. Vigorous gas evolution was observed 20 minutes after heat was applied, before the reaction reached reflux temperature. The mixture was cooled to room temperature, and treated with carbon disulfide (23.96 mL, 397 mmol), causing the color to change to a burnt amber. The reaction was returned to reflux temperature for 2 hours. The mixture was cooled to room temperature, treated with iodomethane (1.570 mL, 25.1 mmol), and stirred at room temperature for 1.5 hours. The reaction was quenched with brine, and the mixture was extracted 3× with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated in-vacuo. The residue was purified over a 8×10 cm silica gel column, eluting with ethyl acetate/hexanes (5%-10%-15%-20% ethyl acetate), to yield the title compound (7.3 g, 17.38 mmol, 83% yield) as an amber oil. MS (ESI+)=421, (M+H)+.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=O)[C:2]2=O.COP([CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[CH3:26])=O)(=O)OC.O.[NH2:28][NH2:29]>>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:28]=[N:29][C:2]3[C@@H:1]4[CH2:7][C@H:4]([C:3]=3[CH:16]=2)[CH2:5][CH2:6]4)=[C:20]([CH3:26])[CH:21]=1
Reactant: COP(=O)(CC(=O)c1ccc(Cl)cc1C)OC
Reactant: NN
Reactant: O=C1C(=O)C2CCC1C2
Solvent: O
Product: Cc1cc(Cl)ccc1-c1cc2c(nn1)[C@H]1CC[C@@H]2C1

Procedure:
MS (EI): 270.2 (M+), yellow waxy solid. Prepared from bicyclo[2.2.1]heptane-2,3-dione, [2-(4-Chloro-2-methyl-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: I[C:2]1[N:11]=[C:10]2[N:4]([CH2:5][CH2:6][C:7]3[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=3[CH:9]2[O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)CCC.[F-].[K+]>C1(C)C=CC=CC=1.O.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>[CH3:19][N:16]1[CH2:17][CH2:18][CH:13]([O:12][CH:9]2[C:8]3[CH:20]=[CH:21][CH:22]=[CH:23][C:7]=3[CH2:6][CH2:5][N:4]3[C:10]2=[N:11][C:2]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:3]3)[CH2:14][CH2:15]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CN1CCC(OC2c3ccccc3CCn3cc(I)nc32)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CN1CCC(OC2c3ccccc3CCn3cc(-c4ccccn4)nc32)CC1
Temperature: 100 °C

Procedure:
To a solution of 2-iodo-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 2A) (50 mg, 0.12 mmoles) in toluene (500 μL) in a screw-capped vial under argon are added 2-(tributylstannyl)pyridine (77 μL, 0.24 mmole), tetrakis(triphenylphosphine)palladium(0) (14 mg, 12 μmole). The reaction mixture is heated at 100° C. overnight. A solution of 10% KF in water is added, and the aqueous phase is extracted three times with CH2Cl2. The organic phase is washed with a solution of 10% KF in water, brine, dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is pre-purified by silica gel chromatography using (CH2Cl2:MeOH:NH4OH) as eluent with a gradient from (99:1:0.1) to (95:5:0.5) and the residue is submitted to a preparative thin-layer chromatography eluting with (CH2Cl2:MeOH:NH4OH) (9:1:1) to afford 4-(1-methylpiperidin-4-yloxy)-2-pyridin-2-yl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=O.C(O)(=O)CC.P(Cl)(Cl)[Cl:16].C(OC(=O)C)(=O)C>>[ClH:16].[NH2:1][C@@H:2]1[C:7](=[O:8])[O:9][C:4](=[O:6])[CH2:3]1
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: ClP(Cl)Cl
Solvent: CCC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cl
Product: N[C@H]1CC(=O)OC1=O

Procedure:
To a suspension of 10 g. of L-aspartic acid in 40 ml. of propionic acid is added, at room temperature with stirring, 3.8 g. of phosphorous trichloride and stirring is continued at that temperature for about 1 1/2 hours. At the end of that time, 5 g. of acetic anhydride is added and the reaction mixture is stirred at room temperature for approximately 8 hours longer. The crystals which separate from the reaction mixture are filtered, washed with ether and dried to afford L-aspartic acid anhydride hydrochloride.
Reaction SMILES: C([N:8]([C@@H:19]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=1)[CH2:20][OH:21])[CH2:9][C@@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[OH:11])C1C=CC=CC=1.CO>[Pd].ClC1C=CC=CC=1>[ClH:18].[ClH:18].[NH2:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][C@H:19]([NH:8][CH2:9][C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[OH:11])[CH2:20][OH:21])=[CH:28][CH:27]=1
Reactant: O=[N+]([O-])c1ccc(C[C@@H](CO)N(Cc2ccccc2)C[C@H](O)c2cccc(Cl)c2)cc1
Agent: [Pd]
Solvent: CO
Solvent: Clc1ccccc1
Product: Cl
Product: Nc1ccc(C[C@@H](CO)NC[C@H](O)c2cccc(Cl)c2)cc1
Reaction time: 2 h
Yield: 312 %

Procedure:
To a solution of (2S)-2-[N-benzyl-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-3-(4-nitrophenyl)-1-propanol (5.33 g) in a mixed solvent of methanol (50 ml) and chlorobenzene (50 ml) was added 10% palladium on activated carbon (50% wet, 1.00 g) and the mixture was hydrogenated at 1 atm for 2 hours. The catalyst was filtered off and washed with methanol. The filtrate was concentrated in vacuo to give (2S)-3-(4-aminophenyl)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-1-propanol dihydrochloride (4.95 g) as a pale yellow solid.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14]/[CH:15]=[C:16](\[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:33]CCl>C(O)C.CC(C)=O>[ClH:33].[CH3:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1/[C:16](/[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[CH:15]\[O:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1
Reactant: CCOC(=O)[C@@H]1CCCN(CCO/C=C(/c2ccccc2)c2ccccc2C)C1
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCO
Product: Cc1ccccc1/C(=C\OCCN1CCC[C@@H](C(=O)O)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
Z-(R)-1-(2-((2-(2-Methylphenyl)-2-phenylethenyl)oxy)ethyl)-3-piperidinecarboxylic acid ethyl ester (2.0 g, 0.0051 mol, prepared similarly to the method described in Example 50) was dissolved in ethanol (8 ml) and 12 N sodium hydroxide solution (1.3 ml) was introduced. After stirring the solution at room temperature for 2 h, 37% hydrochloric acid (ca. 1.8 ml) was added with cooling, followed by dichloromethane (300 ml) and the mixture was dried (Na2SO4). Filtration and evaporation of the filtrate gave a residue, which was co-evaporated with acetone. The solid product was triturated with ethyl acetate, collected by filtratiion and dried in vacuo to give the title compound (0.70 g, 34%).
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:5][CH:6]=[CH2:7])[CH2:3][NH2:4].C(N(C(C)C)CC)(C)C.Cl[C:19]([O:21][CH3:22])=[O:20].O>C(Cl)Cl>[CH3:1][C:2]([CH3:8])([CH2:5][CH:6]=[CH2:7])[CH2:3][NH:4][C:19](=[O:20])[O:21][CH3:22]
Reactant: COC(=O)Cl
Reactant: C=CCC(C)(C)CN
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCC(C)(C)CNC(=O)OC
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A 1 L round-bottom flask under nitrogen was charged with 2,2-Dimethylpent-4-en-1-amine (9.86 g, 87 mmol), diisopropylethylamine (16.73 ml, 96 mmol), and DCM (100 mL) and cooled to 0° C. A solution of methyl chloroformate (7.08 mL, 91 mmol) in DCM (50 mL) was added dropwise. The reaction mixture was warmed to RT, stirred for 24 hours and poured into water. The mixture was extracted with EtOAc (3×). The combined organic portions were washed with brine, dried with anhydrous MgSO4 and filtered, and the solvent was removed from the filtrate by rotary evaporation. The crude product was purified by silica gel chromatography eluting with 70 hexane/30 EtOAc, to give the title compound. 1H NMR (CDCl3): δ 5.85-5.79 (m, 1H), 5.06-5.02 (m, 2H), 4.46 (s, 1H), 3.67 (s, 3H), 3.02-3.00 (m, 2H), 1.98-1.96 (m, 2H), 0.88 (s, 6H) ppm.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26](F)[CH:25]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:42][NH2:43]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:25]=[C:26]3[C:27]([C:30]([NH2:31])=[N:42][NH:43]3)=[CH:28][CH:29]=2)[N:3]=1
Reactant: NN
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)Nc4ccccc4F)C3)nc(N)n2)cc1F
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCC[C@H](C(=O)Nc3ccccc3F)C2)n1
Temperature: 150 °C
Yield: 10.2 %

Procedure:
Into a microwave tube, (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-(2-fluorophenyl)-3-piperidinecarboxamide (191 mg, 0.440 mmol), 3 mL of EtOH, Hunig's base (0.077 mL, 0.440 mmol), and hydrazine anhydrous (0.055 mL, 1.759 mmol) were added, and the resulting yellow mixture was heated at 150° C. for 150 minutes under microwave conditions. The solution turned black. LCMS showed mainly product. The black solids were filtered and the yellow filtrate was evaporated. The yellow residue was dissolved in CH3OH, and purified by HPLC (CH3CN/H2O w/0.1% HCO2H) to afford a formic acid salt of the title compound (20 mg) as a light yellow solid. LC-MS (ES) m/z=447 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.51 (m, 1H), 1.84 (m, 2H), 2.01-2.20 (m, 1H), 3.21-3.24 (m, 2H), 3.44-3.61 (m, 1H), 4.36-4.53 (m, 1H), 4.61-5.09 (m, 1H), 6.97 (m, 1H), 7.17 (m, 3H), 7.39 (s, 1H), 7.67-8.01 (m, 3H), 9.84 (m, 1H), 11.87-12.17 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19](O)=[O:20])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C=O>[N:1]1([C:19]([C@@H:15]2[CH2:16][CH2:17][CH2:18][N:13]([C:11]([O:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:12])[CH2:14]2)=[O:20])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Reactant: C1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)N2CCCC2)C1
Temperature: 30 °C
Reaction time: 16 h

Procedure:
To a solution of pyrrolidine (2.134 g, 30 mmol) in N,N-dimethylformamide (240 mL) was added (R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (6.878 g, 30 mmol). Then hydroxybenzotriazole (1.028 g, 6 mmol), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (5.751 g, 30 mmol), and triethylamine (7.59 g, 75 mmol) were added sequentially. The mixture was stirred at 30° C. for 16 h. The solvent was removed under reduced pressure and an aqueous solution of sodium bicarbonate (200 mL, 0.1M) was added. The mixture was extracted with ethyl acetate (200 mL×3) and the combined organics were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford (R)-tert-butyl 3-(pyrrolidine-1-carbonyl)piperidine-1-carboxylate, which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[N:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=[CH:13][C:12]=1[F:21].[H-].[Na+].[CH2:24](I)[CH3:25]>CN(C=O)C>[CH2:24]([O:9][CH2:8][C:6]1[CH:5]=[C:4]([F:10])[C:3]([C:11]2[N:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=[CH:13][C:12]=2[F:21])=[C:2]([F:1])[CH:7]=1)[CH3:25]
Reactant: CCI
Reactant: COC(=O)c1ccc(F)c(-c2c(F)cc(CO)cc2F)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCc1cc(F)c(-c2nc(C(=O)OC)ccc2F)c(F)c1
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
To a solution of methyl 6-(2,6-difluoro-4-(hydroxymethyl)phenyl)-5-fluoropicolinate (1.0 equiv.) in DMF (0.20 M) (colorless) at 0° C. was added sodium hydride (1.2 equiv.) and the reaction was stirred at 0° C. for 2 min. Ethyl iodide (1.2 equiv.) was added and the reaction was allowed to warm to room temperature. After 1 h, additional 1.0 equiv. of NaH was added and stirred for 15 ml. Reaction was quenched by the addition of sat. Ammonium chloride. The aqueous was acidified with conc HCl to pH3 and extracted with ethyl acetate three times. The organics were combined, dried with MgSO4, filtered and concentrated. The crude mixture was used as is. LC/MS=326.0 (MH+), Rt=0.94 min.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:4][NH:3]1.CN(C=O)C.[H-].[Na+].[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1F)[C:33]#[N:34]>CCOC(C)=O.O>[C:33]([C:32]1[CH:35]=[CH:36][C:37]([N:3]2[CH:4]=[CH:5][C:6]([O:8][CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)=[CH:7][C:2]2=[O:1])=[C:30]([F:29])[CH:31]=1)#[N:34]
Reactant: N#Cc1ccc(F)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc[nH]c(=O)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccn(-c3ccc(C#N)cc3F)c(=O)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
To a mixture of tert-butyl 4-(2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate (730 mg, 2.480 mmol, Step A of Example 132) and DMF (12 mL) at room temperature was added sodium hydride (114 mg, 2.85 mmol). After stirring at room temperature for 1 hr, 3,4-difluorobenzonitrile (345 mg, 2.480 mmol, Aldrich) was added and the reaction mixture was heated at 100° C. for 1.5 hrs and cooled to room temperature. The resulting mixture was diluted with EtOAc and water and the aqueous layer was extracted further with EtOAc (3×). The combined organic extracts were washed with water and brine, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (0-100% EtOAc in hexanes) to give the title compound (602.4 mg, 58.7%) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ 7.47-7.64 (m, 3 H), 7.10 (d, J=7.70 Hz, 1 H), 6.04 (dd, J=7.70, 2.20 Hz, 1 H), 5.96 (d, J=2.20 Hz, 1 H), 4.41-4.55 (m, 1 H), 3.65-3.80 (m, 2 H), 3.27-3.39 (m, 2 H), 1.91-2.04 (m, 2 H), 1.71-1.84 (m, 2 H), 1.48 (s, 9 H). MS (ESI) 358 (M+H—C4H8).
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]=[C:20]([N+]([O-])=O)[CH3:21])=[CH:15][CH:14]=1.N1CCCCC1>C(O)C>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:1]([CH:2]([CH3:4])[CH3:3])[O:5][C:20]=2[CH3:21])=[CH:15][CH:14]=1
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: CC(=Cc1ccc(F)cc1)[N+](=O)[O-]
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)c1c(C(C)C)oc(C)c1-c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl isobutyrylacetate (20.06 g, 126.8 mmol) and 1-fluoro-4-(2-nitro-1-propenyl)benzene (23.0 g, 127 mmol) in ethanol (100 ml) was added piperidine (12.5 ml, 127 mmol) at room temperature, and the mixture was stirred overnight at room temperature and at 80° C. for 1 hr. The solvent of the reaction solution was evaporated under-reduced pressure, water (50 ml) and conc. hydrochloric acid (30 ml) were added to the residue, and the mixture was stirred at room temperature for 1 hr. The reaction solution was extracted twice with ethyl acetate and the collected organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=20/1) to give the objective substance.
Reaction SMILES: [O:1]=[C:2]1[C@H:6]([O:7][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@@H:5]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4](=O)[O:3]1.C(#N)C.[NH2:29][OH:30].O>C1(C)C=CC=CC=1>[OH:30][N:29]1[C:2](=[O:1])[C@H:6]([O:7][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@@H:5]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]1=[O:3]
Reactant: O=C(O[C@H]1C(=O)OC(=O)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: NO
Solvent: O
Solvent: CC#N
Solvent: Cc1ccccc1
Product: O=C(O[C@H]1C(=O)N(O)C(=O)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 4 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
To a 3-neck 5 L round bottom flask fitted with a mechanical stirrer and a Teflon coated temperature probe was added (29) (2.79 mol) followed by acetonitrile (2 L). The suspension was cooled in an ice bath to 4° C., followed by the addition of 50% aqueous hydroxylamine (180 mL, 2.93 mol) over 1 h. The starting material gradually dissolved during the addition and the reaction mixture was warmed to 20° C. and stirred for 1 h. The reaction mixture was concentrated in vacuo, diluted with EtOAc (1 L) and washed with 1 N HCl (2×1 L). The organic phase was separated and concentrated in vacuo to afford a viscous red syrup. The syrup was then heated for two hours in toluene (2.5 L) at 100° C. with azeotropic removal of water. The syrup gradually dissolved and then the product crystallized. After cooling to room temperature the solid was collected by filtration, washed with 10% acetone in hexane (2×1L) and dried in a vacuum oven to afford the title compound (30) (862 g, 2.43 mol, 87% yield) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 5.85 (s, 2H), 7.45 (app. t, 4H), 7.65 (app t, 2H), 8.05 (m, 4H).
Reaction SMILES: N#N.[CH3:3][O:4][C:5](=[O:12])[CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.C(O)(=O)C>[CH3:3][O:4][C:5](=[O:12])[CH2:6][C:7]1[S:8][C:9]([Br:13])=[CH:10][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1cccs1
Agent: N#N
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)Cc1ccc(Br)s1
Temperature: 25 °C
Reaction time: 72 h
Yield: 81.7 %

Procedure:
(The following reaction is carried out in an anhydrous N2 atmosphere.) Dissolve thiophene-2-yl-acetic acid methyl ester (42) (2.0 g, 12.8 mmol) in anhydrous chloroform (9.0 mL) and glacial acetic acid (9.0 mL), add N-bromosuccinimide (2.3 g, 13.0 mmol) in portions and stir the mixture for 3 d at rt. Add water to the reaction mixture, separate layers and extract the aqu. layer with dichloromethane. Wash combined organic layer several times with a 1 M aqu. NaOH and water and once with brine and dry it with Na2SO4. Purify the crude product by preparative radial chromatography (CyH/EtOAc 5+1] to obtain (5-bromo-thiophen-2-yl)-acetic acid methyl ester (43) as a yellow oil (2.46 g, 81%) which is used without any further purification. 1H NMR (400 MHz, CDCl3): 3.71 (s, 3H); 3.75 (s, 2H); 6.67 (d, 1H, J=3.8 Hz); 6.88 (d, 1H, J=3.8 Hz).