Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][CH:12]([F:15])[CH2:13][NH2:14].O>C(#N)C>[F:11][CH:12]([F:15])[CH2:13][NH:14][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: NCC(F)F
Reactant: O=[N+]([O-])c1ccccc1Cl
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1ccccc1NCC(F)F
Reaction time: 24 h
Yield: 95 %

Procedure:
2 ml (19 mM) of 2-Chloronitrobenzene and 2.7 ml (36 mM) of 2,2-difluoroethyl amine in 2 ml of acetonitrile were refluxed under stirring for 24 h. Water was added and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed under vacuum to give 3.65 g of N-(2,2-difluoroethyl)-2-nitroaniline as an orange solid. Yield: 95%.
Reaction SMILES: [C:1]1([C:7]2[C:8]([O:10][C:11](=[O:13])[CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].[Cs+].[C:16]([Si](C)(C)C)([F:19])([F:18])[F:17]>C(#N)C.C(OCC)C>[F:17][C:16]([F:19])([F:18])[C:8](=[O:9])[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH:12][C:11]([OH:10])=[O:13]
Reactant: O=C1C=C(c2ccccc2)C(=O)O1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [Cs+]
Agent: [F-]
Solvent: CCOCC
Solvent: CC#N
Product: O=C(O)C=C(C(=O)C(F)(F)F)c1ccccc1
Reaction time: 1 h
Yield: 86.5 %

Procedure:
To a stirred solution of phenylmaleic anhydride (18.7 g, 0.107 mol) in acetonitrile (180 ml) at 0° C. (ice/water/sodium chloride bath—temperature of the bath −10° C.), was added CsF (18.6 g, 0.127 mol), followed by the drop-wise addition of CF3SiMe3 (18.58 ml, 0.127 mol), under nitrogen. The reaction mixture was stirred for 1 h, and was then diluted with diethyl ether and extracted with 2M sodium hydroxide (200 ml). The separated aqueous layer was acidified to pH=1 by the addition of conc. hydrochloric acid. This mixture was extracted with dichloromethane. The separated organic layer was dried (Na2SO4), and the solvent was evaporated in vacuo to yield D1 (22.6 g, 86%) as a mixture of isomers (80/11 ratio by LCMS). C11H7F3O3 requires 244; Found 243 (M-H−).
Reaction SMILES: C(Cl)Cl.[Al+3].[Cl-].[Cl-].[Cl-].N#N.[CH2:10](Cl)[CH2:11][CH2:12][CH3:13]>>[CH2:13]=[CH:12][CH2:11][CH2:10][CH2:10][CH2:11][CH2:12][CH3:13].[CH2:13]=[CH:12][CH2:11][CH2:10][CH2:10][CH2:11][CH2:12][CH2:13][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCl
Agent: N#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C=CCCCCCC
Product: C=CCCCCCCCCCC
Temperature: 15 °C
Reaction time: 3 h

Procedure:
A two liter reactor is equipped with a stirrer, addition funnel, thermometer, condenser and a cooling bath. A solution of 300 g (2.68 moles) 1-octene, 300 g (1.79 moles) 1-dodecene and 3.9 g (0.042 moles) normal butyl chloride was prepared and charged to the addition funnel. To the reactor was charged 300 ml. dry methylene chloride and 12.0 g anhydrous AlCl3. A N2 atmosphere was maintained throughout the polymerization procedure. The stirred AlCl3 slurry was cooled to 15° C., whereupon a dropwise addition of the comonomer/n-butyl chloride solution was initiated and continued over 3.0 hours into the reactor. The polymerization temperature was maintained at 15° C.±1° C. After the comonomer/n-butyl chloride charge was complete, the polymerization mixture was stirred for an additional 3.0 hours at 15° C.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[NH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:20]([CH:22]1[O:24][CH2:23]1)Cl.[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>CN(C)C=O>[CH2:25]([N:27]([CH2:28][CH3:29])[CH2:20][CH:22]([OH:24])[CH2:23][N:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:17])[CH3:26]
Reactant: O=c1[nH]cc(-c2ccccc2)c2ccccc12
Reactant: ClCC1CO1
Reactant: CCNCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CC(O)Cn1cc(-c2ccccc2)c2ccccc2c1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
A mixture of 6.6 g of 4-phenyl-1(2H)-isoquinolone, 2.9 g of 50% sodium hydride and 80 ml of dimethylformamide was stirred at 60° to 70° C. for 3 hours. 5.5 g of epichlorohydrin was then added dropwise to the reaction solution while cooling and stirring, and the mixture was then stirred at room temperature for 12 hours. The reaction solution was poured into ice-water, and the precipitated crystals were collected by filtration and washed with water. The crystals thus obtained were dissolved in 40 ml of dimethylformamide, 12 ml of diethylamine was added thereto and the mixture was heated at 100° C. for 5 hours in a sealed tube. The residue obtained after distilling off the solvent was dissolved in diethyl ether, and the solution was washed with water and extracted with 5% hydrochloric acid. The extract was rendered neutral with 10% aqueous solution of sodium hydroxide to precipitate crystals which were then collected by filtration and recrystallized from a mixture of ethyl acetate and petroleum ether to obtain 6.5 g (61% yield) of 2-(3-diethylamino-2-hydroxypropyl)-4-phenyl-1(2H)-isoquinolone having a melting point of 106° C. as colorless prisms.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[C:17]([O:21][C:22]([NH:24][CH:25](N)[CH2:26][CH2:27][NH2:28])=[O:23])([CH3:20])([CH3:19])[CH3:18].O[C:31]1C2N=NNC=2C=CC=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>O.CN(C=O)C>[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27][NH:28][C:14](=[O:16])[C:12]([NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])([CH3:13])[CH3:31])=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: Oc1cccc2[nH]nnc12
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)NC(N)CCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCNC(=O)C(C)(C)NC(=O)OCc1ccccc1
Reaction time: 16 h

Procedure:
N-carbobenzyloxyalanine (1.3 g, 5.7 mmol), 3-(N-tertbutoxycarbonylamino)-1,3-propanediamine (1 g, 5.7 mmol), hydroxybenzotriazole (0.88 g, 5.8 mmol), HBTU (2.4 g, 0.63 mmol), and diisopropylethylamine (1.48 g, 11.5 mmol) were added to dry DMF (25 mL) under nitrogen and stirred 16 hours, when the reaction was poured into water (100 mL) and extracted with ethyl acetate. The combined organics were washed with 0.1N HCl and saturated bicarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The reaction mixture was not further purified but carried directly into the next step. Mass Spec (EI): m/z=380.3 (M+H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[C:22]2[C:21]3[CH:20]=[C:19]([OH:23])[C:18]([O:24][CH3:25])=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:12]([CH3:26])[C:11]1=[O:27])[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:35][C:36]1[CH:40]=[CH:39][S:38][CH:37]=1.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[C:22]2[C:21]3[CH:20]=[C:19]([O:23][CH2:35][C:36]4[CH:40]=[CH:39][S:38][CH:37]=4)[C:18]([O:24][CH3:25])=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:12]([CH3:26])[C:11]1=[O:27])[C:5]#[N:6]
Reactant: ClCc1ccsc1
Reactant: COc1cc2ncc3c(c2cc1O)n(-c1ccc(C#N)cc1F)c(=O)n3C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncc3c(c2cc1OCc1ccsc1)n(-c1ccc(C#N)cc1F)c(=O)n3C
Temperature: 50 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
3-Fluoro-4-(8-hydroxy-7-methoxy-3-methyl-2-oxo-2,3-dihydroimidazo[4,5-c]quinolin-1-yl)benzonitrile (80 mg, 220 μmol) was dissolved in N,N-dimethylformamide (4.0 ml) under a dry argon atmosphere. Potassium carbonate (85 mg, 618 μmol) and 3-chloromethylthiophene (112 mg, 845 μmol; prepared from 3-thiophenemethanol using SOCl2 in CH2Cl2) were subsequently added. The reaction mixture was stirred at 50° C. for 18 h overnight. When the reaction was complete, the mixture was poured into water (60 ml), stirred for 30 min and extracted twice with ethyl acetate (75 ml each time). The combined organic phases were washed with water (25 ml), subsequently dried over Na2SO4, filtered with suction and evaporated in vacuo. The residue chromatographed over flash silica gel (solvent gradient ethyl acetate/0-17% by vol. of ethanol), giving 3-fluoro-4-(7-methoxy-3-methyl-2-oxo-8-(thiophen-3-ylmethoxy)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl)benzonitrile (64 mg, 139 μmol), as solid. MS: 461.1 (M+H+), TLC (HPTLC): Rf=0.33 (ethyl acetate/ethanol 5:1, parts by volume).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.[Cl-].[CH3:14][O:15][NH3+:16].N1C=CC=CC=1>C(O)C>[CH3:14][O:15][N:16]=[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:4][CH2:3][CH2:2][Cl:1]
Reactant: O=C(CCCCl)c1ccccc1
Reactant: CO[NH3+]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CCO
Product: CON=C(CCCCl)c1ccccc1
Yield: 84.1 %

Procedure:
A mixture of 1-chloro-4-phenylbutan-4-one (1.83 g, 10 mmol), O-methylhydroxylammonium chloride (1.67 g, 20 mmol), pyridine (1.21 ml, 15 mmol), and ethanol (15 ml) was heated at reflux for 1 hour and then evaporated in vacuo. The residue was partitioned between chloroform and water, and the organic layer was dried (MgSO4) and evaporated in vacuo to give 1-chloro-4-phenylbutan-4-one O-methyloxime (1.78 g, 84%), νmax (neat) 2930, 1445, 1050, 900 cm-1 ; λmax (EtOH) 209 nm (εm 17,200), 253 nm (εm 11,100); δH (CDCl3) 7.3-7.8 (5H, m, aryl), 3.9 (3H, s, OMe), 3.5 (2H, t, H1), 2.9 (2H, t, H3), 2.0 (2H, qn, H2).
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH3:25])=[O:5])C.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:4](=[O:5])[C:6]3[CH:7]=[N:8][C:9]4[C:10]([O:24][CH3:25])=[CH:11][CH:12]=[CH:13][C:14]=4[C:15]=3[N:16]([CH:17]3[CH2:18][CH2:19][CH:20]([CH3:23])[CH2:21][CH2:22]3)[C:34]2=[O:35])=[CH:29][CH:28]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCC(C)CC1
Product: COc1cccc2c1ncc1c(=O)n(-c3ccc(Cl)cc3)c(=O)n(C3CCC(C)CC3)c12
Yield: 74.5 %

Procedure:
3-(4-Chloro-phenyl)-7-methoxy-1-(4-methyl-cyclohexyl)-1H-pyrimido[5,4-c]quinoline-2,4-dione (55 mg) was prepared from 8-methoxy-4-(4-methyl-cyclohexylamino)-quinoline-3-carboxylic acid ethyl ester (0.164 mmol) and 1-chloro-4-isocyanato-benzene (0.25 mmol) following general procedure C. LCMS: m/z 450 [M+1]+.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[NH:4][N:3]=1.Br[CH2:13][CH:14]1[CH2:16][CH2:15]1>>[CH:14]1([CH2:13][N:4]2[C:5]3[C:10](=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=3)[C:2]([I:1])=[N:3]2)[CH2:16][CH2:15]1
Reactant: BrCC1CC1
Reactant: Cc1ccc2[nH]nc(I)c2c1
Product: Cc1ccc2c(c1)c(I)nn2CC1CC1
Yield: 66 %

Procedure:
The title compound was prepared in 66% yield from 3-iodo-5-methyl-indazole and (bromomethyl)cyclopropane according to the general procedure for Preparation 10A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 0.38-0.41 (2H, m), 0.54-0.59 (2H, m), 1.31-1.34 (1H, s), 2.48 (3H, s), 4.24 (2H, d, J=7.2 Hz), 7.23-7.29 (3H, m).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([Cl:20])[CH:3]=1.[CH:21]([NH2:25])([CH2:23][CH3:24])[CH3:22]>>[CH:21]([NH:25][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([Cl:20])[CH:3]=1)([CH2:23][CH3:24])[CH3:22]
Reactant: CCC(C)N
Reactant: O=C(Nc1nc2cc(Cl)cc(Cl)n2n1)c1cccnc1
Product: CCC(C)Nc1cc(Cl)cc2nc(NC(=O)c3cccnc3)nn12
Yield: 13.6 %

Procedure:
The title compound was prepared following procedure and work up described for example 118, but starting from N-(5,7-dichloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B10), 100 mg; 0.32 mmol; 1.0 eq) and sec-butylamine (118 mg; 1.62 mmol; 5.0 eq) to give the title compound as a white solid (15 mg, 13%). HPLC, Rt: 3.07 min. (purity 96.3%). LC/MS, M+(ESI): 344.8, M−(ESI): 342.9.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].F[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[N+:23]([O-:25])=[O:24])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)C1
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)C2)c([N+](=O)[O-])c1
Temperature: 85 °C
Yield: 43.5 %

Procedure:
The trans-(3-amino-cyclopentyl)-carbamic acid tert-butyl ester (420 mg, 2.09 mmol) was mixed with 4-fluoro-3-nitrotoluene (342 mg, 2.2 mmol) and potassium carbonate (915 mg, 6.6 mmol) in DMF (20 mL). The stirring mixture was heated at 85° C. for 16.5 hours. The reaction mixture was evaporated under reduced pressure. The residue was partitioned with 50 mL of dichloromethane and 50 mL of brine. The aqueous phase was extracted again with 50 mL of dichloromethane and each organic extract was washed with a portion of brine. After drying, filtering and evaporation of solvents, the crude mixture was purified on silica gel eluting with ethyl acetate and hexanes to give trans-[3-(4-methyl-2-nitro-phenylamino)-cyclopentyl]-carbamic acid tert-butyl ester as a orange oil (305 mg). 1H-NMR is consistent with the assigned structure. LC-MS showed a single peak, C17H25N3O4 (m/e) calcd 335.1845, obsd 336.2 (M+1).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:19]([O-:21])=[O:20])=[C:6]([CH:8]=[C:9]([CH2:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:10]#[N:11])[CH:7]=1.[O:22]1[CH2:27][CH2:26][CH2:25][O:24][CH:23]1[C:28]1[CH:29]=[C:30]([SH:34])[CH:31]=[CH:32][CH:33]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[O:22]1[CH2:27][CH2:26][CH2:25][O:24][CH:23]1[C:28]1[CH:29]=[C:30]([S:34][C:2]2[CH:3]=[CH:4][C:5]([N+:19]([O-:21])=[O:20])=[C:6]([CH:8]=[C:9]([CH2:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:10]#[N:11])[CH:7]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: Sc1cccc(C2OCCCO2)c1
Reactant: N#CC(=Cc1cc(F)ccc1[N+](=O)[O-])CC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CC(=Cc1cc(Sc2cccc(C3OCCCO3)c2)ccc1[N+](=O)[O-])CC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(5-Fluoro-2-nitro-phenyl)-2-(tetrahydro-pyran-4-ylmethyl)-acrylonitrile (1.2 g, 4.07 mmol) and 3-[1,3]dioxan-2-yl-benzenethiol (0.8 g, 4.07 mmol) were added to a mixture of Cs2CO3 (2.78 g, 8.56 mmol) in DMF (100 mL). The resulting mixture was stirred at room temperature overnight, then diluted with ethyl acetate and washed with H2O. The organic phase was separated, dried with MgSO4, and filtered. The solvent was removed to yield an oil, which was purified by silica column chromatography (40% EtOAc/heptane) to yield an oil.
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]1[CH:22]=[C:21]([C:23](O)=[O:24])[NH:20][N:19]=1.N>>[ClH:1].[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:23]([C:21]3[CH:22]=[C:18]([C:14]4[S:13][CH:17]=[CH:16][CH:15]=4)[NH:19][N:20]=3)=[O:24])[CH2:3]1)[CH2:9]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1cc(-c2cccs2)n[nH]1
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1cc(-c2cccs2)[nH]n1

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 3-(2-thienyl)-1H-pyrazole-5-carboxylic acid (Specs) according to methods A and C; yield 34 mg, 0.08 mmol (33%): 1H NMR (300 MHz, methanol-d4) δ 2.09-2.29 (m, 6H), 2.45 (s, 2H), 3.49 (d, J=13 Hz, 2H), 3.56 (s, 2H), 3.83 (d, J=13 Hz, 2H), 4.29 (s, 1H), 7.02 (s, 1H), 7.12 (dd, J=5, 4 Hz, 1H), 7.43 (dd, J=4, 1 Hz, 1H), 7.48 (dd, J=5, 1 Hz, 1H); MS (DCI/NH3) m/z 329 (M+H)+; Anal. C17H20N4OS.2HCl.0.15H2O.0.05C4H8O2: C, H, N.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:26][C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=2)[C:14]2[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24][CH3:25])=[O:23])=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH2:41][CH3:42])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:26][C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:38])[F:39])[CH:28]=2)[C:14]2[N:15]=[CH:16][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:18][N:19]=2)[CH2:10][C@H:9]1[CH2:41][CH3:42])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(/C=C/C(=O)OC)cn2)CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(CCC(=O)OC)cn2)CN1C(=O)OC(C)(C)C
Yield: 99.2 %

Procedure:
(2R,4S)-4-{(3,5-Bis-trifluoromethyl-benzyl)-[5-((E)-2-methoxycarbonyl-vinyl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 0.33 mmol) is dissolved in EtOH (5 mL) and hydrogenation reaction with 10% Pd/C. The residue is purified by column chromatography on silica gel (eluent: n-hexane/EtOAc) to give (2R,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-(2-methoxycarbonyl-ethyl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (198 mg, 99%).
Reaction SMILES: [C:1]([CH:6]([CH2:10]C#C)[C:7](=O)[CH3:8])([O:3][CH2:4][CH3:5])=O.C(=O)(O)O.[NH2:17][C:18](N)=[NH:19].C(O)C.CC(C)=O>CS(C)=O>[CH3:8][C:7]1[C:6]2[CH:10]=[C:4]([CH3:5])[O:3][C:1]=2[N:17]=[CH:18][N:19]=1
Reactant: N=C(N)N
Reactant: C#CCC(C(C)=O)C(=O)OCC
Agent: O=C(O)O
Solvent: CC(C)=O
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1cc2c(C)ncnc2o1
Temperature: 25 °C
Yield: 59 %

Procedure:
A mixture of 6.0 g 3-carbethoxy-5-hexyn-2-one and 3.6 g guanidine carbonate was heated in 9 ml dimethylsulfoxide under a nitrogen atmosphere at 140° for 4 hours. The ethanol produced in the reaction was removed as it was formed by distillation. After cooling to room temperature, acetone was added then the crystalline solid was collected then rinsed with water to yield 2.6 g of 4,6-dimethylfuro[2,3-d]pyrimidine; m.p. 262°-263°. Absorptions at 2.55 (singlet), 2.82 (singlet) and 6.58 (broadened singlet) ppm in the nuclear magnetic resonance spectrum (60 MHz) indicated the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:17]=[C:16]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][C:12](=[O:32])[N:13]2[C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:31].[CH3:33][C:34]([CH3:36])=O.C([BH3-])#N.[Na+]>CO.CCOC(C)=O.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:17]=[C:16]([CH:18]2[CH2:19][CH2:20][N:21]([CH:34]([CH3:36])[CH3:33])[CH2:22][CH2:23]2)[CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][C:12](=[O:32])[N:13]2[C:24]1[C:25]([Cl:31])=[CH:26][CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: O=c1ccc2c(-c3ccccc3Cl)nc(C3CCNCC3)cc2n1-c1c(Cl)cccc1Cl
Reactant: CC(C)=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)N1CCC(c2cc3c(ccc(=O)n3-c3c(Cl)cccc3Cl)c(-c3ccccc3Cl)n2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 14 mg of 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-piperidin-4-yl-1,6-naphthyridin-2(1H)-one in 1 mL of MeOH was added 0.1 mL of acetone, then 9 mg of sodium cyanoborohydride. The mixture was stirred 5 h at rt, then diluted with 1 mL of EtOAc and 10 mL NaHCO3. The phases were separated and the aqueous phase was extracted with 2×10 mL of EtOAc. The combined organics were washed with 10 mL of brine, dried (Na2SO4), and concentrated. The residue was purified by preparative thin-layer chromatography, eluting with 95:5 CH2Cl2-2M NH3 in MeOH to yield the title compound. Mass spectrum (ESI) 528 (M+1). 1H NMR (500 MHz, CDCl3): selected peaks δ 1.07 (d, J=6.5 Hz, 6H), 1.71 (br s, 2H); 1.99 (br s, 2H); 2.26 (br s, 2H); 2.80 (br s, 2H); 3.02 (br s, 2H).
Reaction SMILES: [O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([NH:14][C@H:15]([C:25]([O:27]C)=[O:26])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:13])[C:2]1=[O:3].[OH-].[Na+]>CO>[O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([NH:14][C@H:15]([C:25]([OH:27])=[O:26])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)=[O:13])[C:2]1=[O:3]
Reactant: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)c1cc2ccccc2oc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C[C@H](NC(=O)c2cc3ccccc3oc2=O)C(=O)O)cc1
Yield: 80.7 %

Procedure:
The same procedures as in Example 90 were carried out from the compound obtained in Example 52 (2.7 g), 1 mol/L of an aqueous sodium hydroxide solution (11 mL), and methanol (110 mL), to give the captioned compound (2.1 g, 80%) as crystals.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][O:9][CH2:8][C:7]2=[O:14]>C(O)C>[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][O:9][CH2:8][CH:7]2[OH:14]
Reactant: O=C1COCc2ccc(Br)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC1COCc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
A solution of sodium borohydride (300 mg, 7.93 mmol) dissolved in a minimum amount of ice cold water was added dropwise at 0° C. to a solution of 6-Bromo-isochroman-4-one (1.49 g, 6.56 mmol) in absolute ethanol (27.0 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The phases were separated and the organic phase washed with water and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure to yield 6-Bromo-isochroman-4-ol (1.44 g, 95%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.40 (dd, J=8.3, 1.8 Hz, 1H), 7.30 (d, J=8.3 Hz, 1H), 7.15 (d, J=1.8 Hz, 1H), 4.63 (ABq, J=15.3 Hz, 2H), 4.49 (d, J=8.6 Hz, 1H), 4.07 (dd, J=12.0, 2.8 Hz, 1H), 3.83 (dd, J=12.0, 2.8 Hz, 1H), 2.60 (d, J=9.2 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:27][CH2:26][CH2:25][C@:9]32[N:13]([CH3:14])[C:12](=[O:15])[N:11]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)[C:10]3=[O:24])=[CH:4][CH:3]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[Cl:23][C:18]1[CH:17]=[C:16]([N:11]2[C:10](=[O:24])[C@:9]3([CH2:25][CH2:26][CH2:27][C@H:8]3[C:5]3[CH:6]=[CH:7][C:2]([C:32]4[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=4)=[CH:3][CH:4]=3)[N:13]([CH3:14])[C:12]2=[O:15])[CH:21]=[C:20]([Cl:22])[CH:19]=1
Reactant: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CCC[C@H]2c1ccc(Br)cc1
Reactant: OB(O)c1ccc(F)cc1
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CCC[C@H]2c1ccc(-c2ccc(F)cc2)cc1
Yield: 14.6 %

Procedure:
Using the procedure described in Example 8 (5R*,6S*)-6-(4-bromophenyl)-3-(3,5-dichlorophenyl)-1-methyl-1,3-diazaspiro[4.4]nonane-2,4-dione (80 mg, 0.17 mmol) (Example 1) was reacted with 4-fluorophenylboronic acid (71.4 mg, 0.51 mmol) to yield the above-titled compound (12 mg) as a white solid. 1H NMR (CDCl3): 7.45-7.55 (4H, m), 7.05-7.25 (5H, m), 6.62 (2H, m), 3.46 (1H, dd, J1=12.9 Hz, J2=6.3 Hz), 3.18 (3H, s), 2.5-2.75 (1H, m), 1.85-2.45 (5H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:13])=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.C([O:18][N:19]=O)CCC.Cl>CO>[CH3:1][O:2][C:3]1[C:4]([CH3:13])=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7](=[N:19][OH:18])[CH2:6]2
Reactant: COc1ccc2c(c1C)CCC2=O
Reactant: CCCCON=O
Agent: Cl
Solvent: CO
Product: COc1ccc2c(c1C)CC(=NO)C2=O
Reaction time: 0.5 h

Procedure:
To a solution of 5-Methoxy-4-methyl-indan-1-one (3.1 g) in MeOH at 40° C. was added n-butylnitrite (2.5 mL) followed by concentrated HCl (2.3 ml). The solution was stirred for 30 min during which time a precipitate was formed. The precipitate was collected and dried to yield the crude product as a white solid.