Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>CO.C1COCC1.[Ni]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2ccc([N+](=O)[O-])cn2)cc1OC
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2ccc(N)cn2)cc1OC
Reaction time: 15 h

Procedure:
To a mixture of 2-(3,4-dimethoxyphenyl)-5-nitropyridine (Interchim, Montlucon, France, 2.85 g, 10.95 mmol) in MeOH (27 ml) and THF (27 ml), Ra/Ni catalyst (1.10 g, 10.95 mmol) was added and shaked under hydrogen at rt for 15 h. After that, the RM was filtered over celite, the catalyst was washed with MeOH and the filtrate was evaporated to dryness to give the title compound as an off-white solid. (HPLC: tR 2.22 min (Method A); M+H=231 MS-ES)
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@H:10](O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([N:17](CC)CC)C.CS(Cl)(=O)=O.O>ClCCl>[CH2:1]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@H:10]([C:15]#[N:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H]1CN(Cc2ccccc2)C[C@H]1O
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: C[C@H]1CN(Cc2ccccc2)C[C@H]1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
cis-1-Benzyl-3-hydroxy-4-methylpyrrolidine (6.81 g) was dissolved in dichloromethane (70 mL). While the solution was chilled in a dry ice/acetone bath, triethylamine (5.21 mL) was added, followed by dropwise addition of methanesulfonyl chloride (2.89 mL) and stirring for 1 hour. Subsequently, water (50 mL) was added and the mixture was allowed to warm to room temperature. The dichloromethane layer was separated and the aqueous layer was extracted with dichloromethane (50 mL). The dichloromethane layers were combined, washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in acetonitrile (180 mL). To this solution, tetrabutylammonium cyanide (23.9 g) was added and the mixture was refluxed for 7 hours. Subsequently, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (300 mL). This solution was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (hexane: ethyl acetate=1:1) to give cis-1-benzyl-4-methyl-3-pyrrolidinecarbonitrile as a brown oil (4.61 g).
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(N(CC)CC)C.C[O:17][C:18](=O)[N:19]=[C:20](SC)[C:21]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([O:43][CH2:44][CH3:45])[CH:36]=1)=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1>CN(C=O)C>[CH2:44]([O:43][C:37]1[CH:36]=[C:35]([CH:21]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:33]=[C:32]([CH3:34])[O:31][N:30]=3)=[CH:25][CH:24]=2)[C:20]2[NH:19][C:18](=[O:17])[N:1]([C:3]3[N:8]=[CH:7][CH:6]=[CH:5][N:4]=3)[N:2]=2)[CH:40]=[CH:39][C:38]=1[O:41][CH3:42])[CH3:45]
Reactant: NNc1ncccn1
Reactant: CCOc1cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)ccc1OC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)ccc1OC
Temperature: 85 °C
Reaction time: 10 h
Yield: 38.3 %

Procedure:
After adding 230 mg of 2-hydrazinopyrimidine and 293 μl of triethylamine to a 50 ml DMF solution containing 983 mg of {2-(3-ethoxy-4-methoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester, the mixture was stirred at 85° C. for 10 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 30 ml of a methanol:THF=1:1 mixed solvent. After adding 420 μl of acetic acid and 657 mg of sodium cyanotrihydroborate to the reaction mixture, it was stirred at room temperature for 5 hours. Ethyl acetate was added to the reaction mixture which was then filtered through a small amount of NAM silica gel, and the silica gel was washed with ethyl acetate-methanol. The filtrate was concentrated under reduced pressure, and the residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (400 mg) as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([CH3:12])([CH3:11])[CH3:10].[C:13](Cl)([Cl:15])=[S:14].[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:15][C:13]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:4]=1)=[S:14]
Reactant: CC(C)(C)c1cc(O)ccc1Br
Reactant: S=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc(OC(=S)Cl)ccc1Br
Temperature: 25 °C
Yield: 66.7 %

Procedure:
To 50 ml of chloroform were dissolved 11.5 g of 4-bromo-3-tert-butylphenol and 6.5 g of thiophosgene, and 60 ml of 1-N sodium hydroxide aqueous solution were added dropwise thereto with stirring at room temperature. After completion of this dropwise addition, the mixture was subjected to stirring over a period of 3 hours at room temperature. From the reaction mixture was separated chloroform layer, which was thereafter dried over anhydrous calcium chloride and then chloroform was distilled off therefrom. The residue was purified through a column chromatography (employing silica gel as carrier and hexane as developing solvent) to give 10.3 g of O-4-bromo-3-tert-butylphenyl chlorothioformate.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:38]>>[Cl:38][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1CCO
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)NS(=O)(=O)c1ccccc1CCCl

Procedure:
A solution of 32.5 g of the alcohol from Example 1 and 32.5 g triphenylphosphine in 244 ml of carbon tetrachloride was stirred at room temperature and under an atmosphere of nitrogen for 72 hours. Excess carbon tetrachloride was removed in vacuo to give 83 g of a crude yellow oil. Purification by silica gel chromatography (hexanes-20% ethyl acetate) afforded a colorless viscous oil which crystallized on standing. The product was isolated by trituration with hexanes, filtration, and drying. The yield of pure 2-(2-chloroethyl)-N-(1,1-dimethylethyl)benzenesulfonamide, m.p. 64°-65° C., was 15.9 g.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]([CH2:11][CH2:12][OH:13])[C:9]#[N:10])[CH:5]=[CH:4][CH:3]=1.[NH2:14][C:15]1[S:16][C:17]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([OH:32])([CH3:31])[CH3:30])=[CH:25][C:24]=2[F:33])=[CH:18][C:19]=1[C:20]([NH2:22])=[O:21]>>[C:9]([CH:8]([C:6]1[N:7]=[C:2]([NH:14][C:15]2[S:16][C:17]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([OH:32])([CH3:30])[CH3:31])=[CH:25][C:24]=3[F:33])=[CH:18][C:19]=2[C:20]([NH2:22])=[O:21])[CH:3]=[CH:4][CH:5]=1)[CH2:11][CH2:12][OH:13])#[N:10]
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: N#CC(CCO)c1cccc(Br)n1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(C(C#N)CCO)n3)s2)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 1 using 2-(6-bromopyridin-2-yl)-4-hydroxybutanenitrile (97 mg, 0.40 mmol) and 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (118 mg, 0.40 mmol) as starting materials.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1Cl.[F:9][C:10]([F:15])([F:14])[C@@H:11]([OH:13])[CH3:12]>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:13][C@@H:11]([CH3:12])[C:10]([F:15])([F:14])[F:9]
Reactant: Clc1ccncc1Br
Reactant: C[C@H](O)C(F)(F)F
Product: C[C@H](Oc1ccncc1Br)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 78a, using 3-bromo-4-chloropyridine (CAN 36953-42-1) and (S)-1,1,1-trifluoropropan-2-ol (CAN 3539-97-7) as starting materials and isolated (28 g, 82%) as a yellow oil; MS (ESI, m/z): 270.4 (M+H+).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH:3]=O.O.[C:9]([C:13]1[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=[CH:15][C:14]=1[OH:23])([CH3:12])([CH3:11])[CH3:10].CNC>CO>[C:9]([C:13]1[C:14]([OH:23])=[C:15]([CH2:3][C:2]([CH3:1])([CH3:7])[CH:5]=[O:6])[CH:16]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:18]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: CC(C)(C=O)CO
Agent: CNC
Solvent: O
Solvent: CO
Product: CC(C)(C=O)Cc1cc(C(C)(C)C)cc(C(C)(C)C)c1O
Reaction time: 20 h
Yield: 61 %

Procedure:
125 g (1 mol) of 80% strength aqueous 2,2-dimethyl-3-hydroxypropanal (crude mixture from the synthesis, reduced to a water content of 20% by distillation), 185 g (0.9 mol) of 2,4-di-t-butylphenol, 24 g (0.22 mol) of 40% strength aqueous dimethylamine and 700 g of methanol are reacted in a stirred autoclave under autogenous pressure of 20-30 bar at 160° C. for 20 h and then at 180° C. for 20 h. Workup of the reaction mixture by distillation yields 159 g (61%) of 3-(3,5-di-t-butyl-2-hydroxyphenyl)-2,2-dimethylpropanal (boiling point 115°-116° C.).
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2([CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4]1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.CCOC(C)=O>[CH2:14]([O:13][CH:10]1[CH2:11][CH2:12][C:7]2([O:6][CH2:5][CH2:4][O:3]2)[CH2:8][CH2:9]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OC1CCC2(CC1)OCCO2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1ccc(COC2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of NaH (60%, 4.05 g, 101 mmol) in DMF (50 mL) was added 1,4-dioxaspiro[4.5]decan-8-ol (10 g, 63 mmol) dropwise at 0° C. The reaction mixture was allowed to warm to room temperature, and treated with benzyl bromide (9.02 mL, 76 mmol). The mixture was heated to 50° C. overnight, diluted with EtOAc, and washed with water (×5). The organic layer was dried, concentrated, and purified by flash chromatography to afford the title compound.
Reaction SMILES: [Na].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.[C:13](OCC)(=[O:16])[CH:14]=[CH2:15]>C(O)C.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:15][CH2:14][C:13](=[O:16])[CH2:11][C:10]2=[O:12])=[CH:7][CH:8]=1
Reactant: CC(=O)Cc1ccc(F)cc1
Reactant: C=CC(=O)OCC
Agent: [Na]
Solvent: O
Solvent: CCO
Product: O=C1CCC(c2ccc(F)cc2)C(=O)C1
Yield: 10.4 %

Procedure:
Sodium (0.3 g, 0.013 moles) was dissolved in ethanol (50 ml) and 4-Fluorophenylacetone (2.0 g, 0.013 moles) was added in ethanol (10 ml). Ethyl acrylate (1.3 g, 0.013 moles) was and the reaction mixture was heated at reflux overnight. The reaction mixture was allowed to cool and evaporated under reduced pressure to give a brown gum. Dissolved in water and washed with diethyl ether. The aqueous layer was acidified to pH2 with conc. Hydrochloric acid and extracted with dichloromethane. The extracts were combined and washed with water. Dried over anhydrous magnesium sulphate and filtered. The filtrate was evaporated to give an orange oil. (1.7 g) This was purified using a silica column eluted with dichloromethane:ethyl acetate 8:2 and then dichloromethane:ethyl acetate 2:1 to give a colorless gum. (0.428 g) This was triturated with diethyl ether/isohexane to give 4-(4-Fluorophenyl)cyclohexane-1,3-dione (0.28 g) as a white solid.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][CH2:3][C:4]([O-])=[O:5].C1N=CN(C(N2C=NC=C2)=O)C=1.O/[N:23]=[C:24](\[NH2:32])/[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[CH2:25]([C:24]1[N:32]=[C:4]([CH2:3][CH2:2][C:1]([O:8][CH3:9])=[O:7])[O:5][N:23]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: N/C(Cc1ccccc1)=N\O
Reactant: COC(=O)CCC(=O)[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: COC(=O)CCc1nc(Cc2ccccc2)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.7 %

Procedure:
Butanedioic acid, monomethyl ester (4.0 g, 30.3 mmole) and CDI (5.40 g, 33.3 mmole) were dissolved in anhydrous DMF (15 ml). After stirring the solution at room temperature for 3 hours, (1Z)—N′-hydroxy-2-phenylethanimidamide (5.0 g, 33.3 mmole) was added and the solution heated at 90° C. for 20 hours. After evaporation of solvent, the residue was dissolved in EtOAc. The organic phase was washed with water and brine, dried over Na2SO4. After filtration and evaporation of solvent, the residue was purified by flash chromatography on silica gel eluted with EtOAc/Hexane (25/75). The purification gave 5.2 g (69.7%) of product as light yellowish oil. LCMS calculated for C13H15N2O3 (M+H): 247.1. found 247.0.
Reaction SMILES: C(N(CC)C(C)C)(C)C.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:53]1[N:57]2[CH:58]=[C:59]([C:62]3[CH:71]=[CH:70][C:65]([C:66]([NH:68][CH3:69])=[O:67])=[C:64]([F:72])[CH:63]=3)[CH:60]=[N:61][C:56]2=[N:55][CH:54]=1.[N:73]1[C:82]2[C:77](=[CH:78][C:79]([SH:83])=[CH:80][CH:81]=2)[CH:76]=[CH:75][CH:74]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:72][C:64]1[CH:63]=[C:62]([C:59]2[CH:60]=[N:61][C:56]3[N:57]([C:53]([S:83][C:79]4[CH:78]=[C:77]5[C:82](=[CH:81][CH:80]=4)[N:73]=[CH:74][CH:75]=[CH:76]5)=[CH:54][N:55]=3)[CH:58]=2)[CH:71]=[CH:70][C:65]=1[C:66]([NH:68][CH3:69])=[O:67]
Reactant: Sc1ccc2ncccc2c1
Reactant: CNC(=O)c1ccc(-c2cnc3ncc(Br)n3c2)cc1F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(-c2cnc3ncc(Sc4ccc5ncccc5c4)n3c2)cc1F
Temperature: 100 °C

Procedure:
N,N-Diisopropylethylamine (70 μL, 0.4 mmol), tris(dibenzylideneacetone)-dipalladium(0) (4.58 mg, 0.0050 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (5.79 mg, 0.010 mmol) was added successively to a solution of 4-(3-bromoimidazo[1,2-a]pyrimidin-6-yl)-2-fluoro-N-methylbenzamide (69.8 mg, 0.2 mmol) and quinoline-6-thiol (32.2 mg, 0.2 mmol) in 1,4-dioxane (0.42 mL) in a microwave tube. The tube was sealed and degassed three times, and heated to 100° C. overnight. After cooling, the reaction mixture was diluted with methanol, and filtered. The filtrate was purified by RP-HPLC (pH 10) to give the desired product. LCMS: (M+H)=430.0.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[C:12]([NH:14][CH2:15][CH2:16][O:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=O)=[CH:20][CH:19]=1)=[O:13].[NH2:29][OH:30].[OH-].[Na+].Cl>CO.C1COCC1>[OH:30][NH:29][C:22](=[O:24])[C:21]1[CH:26]=[CH:27][C:18]([O:17][CH2:16][CH2:15][NH:14][C:12]([C:4]2[O:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:3]=2[N:2]([CH3:1])[CH3:28])=[O:13])=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc(OCCNC(=O)c2oc3ccccc3c2N(C)C)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)c1c(C(=O)NCCOc2ccc(C(=O)NO)cc2)oc2ccccc12
Reaction time: 8 h

Procedure:
To a solution of crude methyl 4-[2-(3-dimethylaminobenzofuran-2-ylcarbonylamino)-ethoxy]-benzoate in MeOH and THF was added excess aqueous hydroxylamine solution and NaOH(aq.) to give pH 10-11. The reaction mixture was stirred overnight and then neutralized to pH 7-8 with aqueous hydrochloric acid and concentrated in vacuo. The residue was dissolved in acetonitrile and water and purified with prep HPLC to give the title compound (107 mg). 1H NMR (400 MHz, DMSO-d6) δ 9.88 (m, 1H), 9.31 (t, J=6.0 Hz, 1H), 8.04 (d, J=7.6 Hz, 1H), 7.70 (m, 3H), 7.57 (t, J=7.6 Hz, 1H), 7.45 (t, J=7.6 Hz, 1H), 6.99 (d, J=9.2 Hz, 2H), 4.76 (d, J=4.8 Hz, 2H), 4.23 (t, J=6.0 Hz, 2H), 3.71 (m, 2H), 2.84 (s, 3H), 2.83 (s, 3H). EM (calc.): 397.2; MS (ESI) m/e (M+1H)+: 398.1, (M−1H)−: 396.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31](OCC)=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:37][CH2:38][C@H:39]([OH:41])[CH3:40]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31]([NH:37][CH2:38][C@H:39]([OH:41])[CH3:40])=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O
Reactant: C[C@@H](O)CN
Product: C[C@@H](O)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(2-oxohexahydro-1H-azepin-1-yl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (2R)-1-amino-2-propanol using methods similar to Example 563 to provide an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.06-1.12 (m, 4 H), 1.54 (d, J=5.05 Hz, 4 H), 1.60-1.75 (m, 4 H), 2.36-2.45 (m, 2 H), 3.15-3.25 (m, 1 H), 3.32-3.47 (m, 4 H), 3.82 (ddd, J=10.84, 6.63, 4.42 Hz, 1 H), 4.15-4.24 (m, 4 H), 4.96 (d, J=4.84 Hz, 1 H) 7.10-7.18 (m, 2 H), 7.38-7.44 (m, 2 H), 8.00 (d, J=1.26 Hz, 1 H), 8.56 (d, J=1.47 Hz, 1 H), 10.44 (t, J=5.58 Hz, 1 H), 17.21 (s, 1 H); ES+ MS: 525 (M+H+).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][NH:11][C:12]=2[CH:13]([CH3:15])[CH3:14])[CH:5]=[CH:4][N:3]=1.[CH3:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20]>CS(C)=O.CCOC(C)=O>[CH:13]([C:12]1[NH:11][N:10]=[CH:9][C:8]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[CH3:16])[CH:7]=1)([CH3:15])[CH3:14]
Reactant: Cc1ccccc1CN
Reactant: CC(C)c1[nH]ncc1-c1ccnc(F)c1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1ccccc1CNc1cc(-c2cn[nH]c2C(C)C)ccn1
Temperature: 150 °C
Reaction time: 8 h
Yield: 40.9 %

Procedure:
To a solution of 2-fluoro-4-(5-isopropyl-1H-pyrazol-4-yl)-pyridine (30 mg, 0.15 mmol) in anhydrous DMSO (0.25 mL) is added 2-methyl-benzylamine (37 uL, 0.3 mmol). The reaction mixture is stirred at 150° C. overnight, diluted with EtOAc, and washed with water and brine. The organic layer is dried over sodium sulfate and concentrated in vacuo. The crude product is purified by preparative HPLC to provide 18.8 mg of [4-(5-isopropyl-1H-pyrazol-4-yl)-pyridin-2-yl]-(2-methyl-benzyl)-amine. (Example 1)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:26])[CH:9]2[CH2:13][CH2:12][C:11]3([CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]3)[CH2:10]2)[C:5]([Cl:27])=[CH:4][N:3]=1.Cl.[CH3:29][N:30]1[CH:34]=[C:33]([NH2:35])[CH:32]=[N:31]1.CCN(C(C)C)C(C)C>CCCCO>[Cl:27][C:5]1[C:6]([N:8]([CH3:26])[CH:9]2[CH2:13][CH2:12][C:11]3([CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[CH2:14]3)[CH2:10]2)=[N:7][C:2]([NH:35][C:33]2[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=2)=[N:3][CH:4]=1
Reactant: Cn1cc(N)cn1
Reactant: CN(c1nc(Cl)ncc1Cl)C1CCC2(CCCN(C(=O)OC(C)(C)C)C2)C1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1nc(Nc2cnn(C)c2)ncc1Cl)C1CCC2(CCCN(C(=O)OC(C)(C)C)C2)C1
Temperature: 150 °C
Reaction time: 8 h
Yield: 52.1 %

Procedure:
To a suspension of tert-butyl 2-((2,5-dichloropyrimidin-4-yl)(methyl)amino)-7-azaspiro[4.5]decane-7-carboxylate (470 mg, 1.13 mmol) and 1-methyl-1H-pyrazol-4-amine hydrochloride (235.7 mg, 1.76 mmol) in n-BuOH (5 mL) was added DIPEA (482.6 g, 3.74 mmol). The reaction mixture was stirred at 150° C. in a sealed tube overnight and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/1) to give the title compound as a white solid (280 mg, 52.0%).
Reaction SMILES: Cl.[C:2]1([CH:8]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([OH:11])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[N:43]12[CH2:50][CH2:49][CH:46]([CH2:47][CH2:48]1)[C@@H:45](O)[CH2:44]2>C1COCC1>[C:2]1([CH:8]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([O:11][C@@H:45]2[CH:46]3[CH2:49][CH2:50][N:43]([CH2:48][CH2:47]3)[CH2:44]2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(O)C(c1ccccc1)N1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(c1ccccc1)N1CCCCC1
Temperature: 25 °C
Yield: 3.6 %

Procedure:
2-Phenyl-2-(piperidin-1-yl)acetic acid hydrochloride (0.87 g, 3.40 mmol) was suspended in dry THF (34.0 ml) and, while stirring at room temperature, DCC (1.40 g, 6.80 mmol), HOBT (1.04 g, 6.80 mmol) and (R)-quinuclidin-3-ol (1.30 g, 10.21 mmol) were sequentially added. The white suspension was stirred at the same temperature overnight (UPLC-MS: complete conversion). THF was evaporated and the residue was taken up with EtOAc (30 ml) and washed with water (20 ml) and then with a sat. NaHCO3 (20 ml). The organic phase was dried over Na2SO4, filtered was evaporated. The crude was purified by flash chromatography (DCM/MeOH/NH4OH=98/2/0.2 to 97/3/0.3) to obtain (R)-quinuclidin-3-yl 2-phenyl-2-(piperidin-1-yl)acetate (40 mg, 40% yield) as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[C:15]([NH2:16])=[CH:14][C:12](=[O:13])[NH:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][CH2:18][CH2:19]Br.[OH-].[Na+]>C(O)C>[CH2:1]([N:8]1[C:15]([NH2:16])=[CH:14][C:12](=[O:13])[N:11]([CH2:17][CH2:18][CH3:19])[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cc(=O)[nH]c(=O)n1Cc1ccccc1
Reactant: CCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCn1c(=O)cc(N)n(Cc2ccccc2)c1=O
Yield: 44.6 %

Procedure:
3.0 g (0.014 mol) of 1-benzyl-6-aminouracil are stirred for 3 hours at 70° C. with 2.2 g (0.018 mol) of n-propyl bromide, 4.2 ml of 15% sodium hydroxide solution and 7 ml of ethanol. The mixture is poured onto ice and extracted with methylene chloride. The organic phases are dried and evaporated down. The residual oil is crystallised from a mixture of methylene chloride and methanol. 1.62 g of the title compound are obtained in the form of white crystals (47% of theory), m.p. 189°-192° C.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([C:27](=S)[NH2:28])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:30](N)[CH2:31][NH2:32]>O1CCCC1>[Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([C:27]2[NH:28][CH2:30][CH2:31][N:32]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: NCCN
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](C(N)=S)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](C2=NCCN2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (2S, 4R)-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)-2-thiocarbamoylpyrrolidine (1.5 g) in tetrahydrofuran (20 ml) was added ethylenediamine (1.25 ml) at 0° C. After stirring at room temperature for 24 hours, the mixture was evaporated, extracted with ethyl acetate, and washed with water and brine successively. The dried organic layer was evaporated, and the obtained oil was subjected to a column chromatography on silica gel and eluted with a mixture of dichloromethane, methanol and triethylamine (90:10:1, V/V/V) to give (2S,4R) -4-t-butyldimethylsilyloxy -2-(2-imidazolin-2-yl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.2 g).