Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][O:18][C:19]3[N:24]=[CH:23][N:22]=[C:21]([NH2:25])[C:20]=3[NH2:26])=[CH:12][CH:11]=2)[CH:4]=1.[CH:29]([CH:31]=O)=O>CCO>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][O:18][C:19]3[C:20]4[C:21](=[N:25][CH:29]=[CH:31][N:26]=4)[N:22]=[CH:23][N:24]=3)=[CH:14][CH:15]=2)[CH:4]=1
Reactant: O=CC=O
Reactant: Nc1ncnc(OCCc2ccc(Oc3cc(C(F)(F)F)ccn3)cc2)c1N
Solvent: CCO
Product: FC(F)(F)c1ccnc(Oc2ccc(CCOc3ncnc4nccnc34)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
6-{2-[4-(4-Trifluoromethylpyridin-2-yloxy)-phenyl]-ethoxy}-pyrimidine-4,5-diamine (75 mg, 0.19 mmol) was combined with 50% aqueous glyoxal solution (1 mL) in EtOH (5 mL) and stirred overnight at 25° C. The solution was evaporated and the residue extracted with CH2Cl2. The CH2Cl2 layer was washed with H2O and concentrated in vacuo. The residue was recrystallized from hot MeCN to give 4-{2-[4-(4-trifluoromethyl-pyridin-2-yloxy)-phenyl]-ethoxy}-pteridine (16 mg, 20%): mp 172-173° C.; EIMS m/z 413; 1H NMR (300 MHz, CDCl3) δ 9.24 (s, 1H), 9.07 (s, 1H), 9.02 (s, 1H), 8.30 (s, 1H), 7.43 (d, J=9.5 Hz, 2H), 7.28 (d, J=9.0 Hz, 2H), 4.63 (t, 6.8 Hz, 2H), 3.17 (t, J=7.0 Hz, 2H).
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][CH:5]([NH:8][NH2:9])[CH2:4][CH2:3]1.C(O[CH:13]=[C:14]([C:20]#[N:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C.C([O-])(=O)C.[Na+]>C(O)C>[CH2:18]([O:17][C:15]([C:14]1[CH:13]=[N:9][N:8]([CH:5]2[CH2:6][CH2:7][O:2][CH2:3][CH2:4]2)[C:20]=1[NH2:21])=[O:16])[CH3:19]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: NNC1CCOCC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnn(C2CCOCC2)c1N
Temperature: 82.5 °C
Yield: 92.3 %

Procedure:
(Tetrahydro-pyran-4-yl)-hydrazine hydrochloride (1.975 g, 12.94 mmol), ethyl (ethoxymethylene)-cyanoacetate (1.958 g, 11.57 mmol) and sodium acetate (1.370 g; 16.70 mmol) were combined in ethanol (16 mL). The mixture was heated at 80-85° C. for 17 hours. After cooling to room temperature, the reaction was concentrated and the residue was partitioned between methylene chloride and water. The organic phase was separated and washed with water and then brine. Each aqueous phase was back extracted with methylene chloride. The two organic phases were combined, dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography eluting with 60-100% ethyl acetate/hexanes to give 5-amino-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (2.554 g, 92%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.C1(C)C=C(C)C=C(C)C=1S(O[NH2:22])(=O)=O.[Br:24][C:25]1[O:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1>>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:22]=[C:29]([C:28]3[O:31][C:25]([Br:24])=[CH:26][CH:27]=3)[N:9]=[C:4]2[CH:3]=1
Reactant: O=Cc1ccc(Br)o1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: Nc1cc(Br)cc(N)n1
Product: Nc1cc(Br)cc2nc(-c3ccc(Br)o3)nn12

Procedure:
The title compound, MS m/e (%): 359 (M++1, 100), was prepared in accordance with the general method of example 63 from 4-bromo-pyridine-2,6-diamine, O-mesitylene-sulfonylhydroxylamine, and 5-bromo-furfural. The purification was performed with reversed phase HPLC eluting with an acetonitrile/water gradient.
Reaction SMILES: C1COCC1.C([Li])CCC.[CH3:11][C:12]#[N:13].C([O:16][C:17]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)=O)C>O>[O:16]=[C:17]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)[CH2:11][C:12]#[N:13]
Reactant: CC#N
Reactant: CCOC(=O)c1cccs1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: N#CCC(=O)c1cccs1
Temperature: -50 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
To a flask charged with THF (250 ml) was added dropwise n-butyl lithium (18.4 mL, 46 mmol) at −78° C. under a N2 atmosphere. After addition the resulting solution warmed to −50° C. and dry MeCN (1.86 g, 45 mmol) was added slowly. After 1 h, the reaction was cooled to −78° C. and was treated with thiophene-2-carboxylic acid ethyl ester (6.93 g, 44.5 mmol). After stirring for 1 h the resulting mixture was warmed to RT and stirred for 1 h. Water was added dropwise at 0° C. to quench the reaction and the solution was extracted with ethyl acetate (3×200 mL). The organic layers were combined, washed with brine, dried (Na2SO4) and the solvent was evaporated under reduced pressure to give a solid residue, which was re-crystallized from CH2Cl2. After the solid was collected by filtration, they were redissolved in ethyl acetate (100 mL), and acidified with dilute hydrochloride (2N). The aqueous layer was extracted with ethyl acetate (3×200 mL) and the combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated to yield 3-oxo-3-thiophen-2-yl-propionitrile (4.7 g, yield=70%) as a yellow solid, which was used directly in the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=O)=[CH:4][CH:3]=1.[CH2:11]([N:17](CCCCCC)CCCCCC)[CH2:12]CCCC.C(#N)C=C>O1CCOCC1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[CH:12][C:11]#[N:17])=[CH:4][CH:3]=1
Reactant: CCCCCCN(CCCCCC)CCCCCC
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: C1COCCO1
Solvent: C=CC#N
Product: N#CC=Cc1ccc(F)cc1
Yield: 17.9 %

Procedure:
The procedure described in Example 1 is repeated, except that 15.86 g (0.1 mol) of 4-fluorobenzoyl chloride, 26.95 g (0.1 mol) of tri-n-hexylamine, 6.53 g (0.125 mol) of acrylonitrile and 0.575 g (0.001 mol) of bis-(dibenzylidene-acetone)-palladium(O) in 50 ml of dioxane are used. After a reaction time of 33 hours at 100° C., 2.63 g (0.0179 mol) of 4-fluorocinnamonitrile are obtained, corresponding to a yield of 17.9% of theory; analysis for C9H6FN (molecular weight 147): calculated C 73.46%, H 4.11%, N 9.52%; found C 73.16%, H 4.19%, N 9.61%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:14])[CH:12]=2)[NH:7][CH:6]=1)=[O:4].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:14])[CH:12]=2)[N:7]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=1)=[O:4]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1c[nH]c2ccc(Cl)cc12
Product: COC(=O)c1cn(Cc2ccccc2)c2ccc(Cl)cc12

Procedure:
Prepare by a method similar to Example 48 using 5-chloro-1H-indole-3-carboxylic acid methyl ester and benzyl bromide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:31][OH:32])=[C:8]2[C:13]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[C:12]([C:28]#[N:29])[CH:11]=[N:10][N:9]2[CH:30]=1)=[O:5])[CH3:2]>C(Cl)(Cl)Cl.O=[Mn]=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH:31]=[O:32])=[C:8]2[C:13]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][CH:20]=3)=[C:12]([C:28]#[N:29])[CH:11]=[N:10][N:9]2[CH:30]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2c1CO
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2c1C=O
Temperature: 55 °C
Yield: 93.8 %

Procedure:
To a solution of compound 16C (21.4 mg, 0.05 mmol) in chloroform (1 mL) was added MnO2 (<5 micron, activated, 17 mg, 0.20 mmol). The reaction was heated at 55° C. overnight, cooled to room temperature and purified by flash chromatography on a silica gel column (0-2% EtOAc/CH2Cl2) to give compound 18 as a yellow solid (20 mg, 94%). HPLC: 94% at 2.20 min (retention time) (PrimeSphere 5u C18-HC column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm). MS (ES): m/z 427.0 [M+H]+.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1>C(Cl)(Cl)Cl>[ClH:3].[Cl:3][CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1
Reactant: OCC1CCNCC1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cl
Product: ClCC1CCNCC1
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of 58 ml of thionyl chloride in 250 ml of chloroform, there is added dropwise a solution of 45 g (0.39 mole) of 4-hydroxymethylpiperidine in 200 ml of chloroform. After stirring for 1 hour under reflux, the reaction mixture is evaporated in a vacuum and the residue is triturated with diethyl ether. There are obtained 54.2 g of 4-chloromethylpiperidine hydrochloride (88% of theory); m.p. 130°-132° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[Si:29]([C:33]#[CH:34])([CH3:32])([CH3:31])[CH3:30].C(N(CC)CC)C.N#N>CN(C=O)C.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.[Cu]I>[CH3:1][O:2][C:3](=[O:28])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:34]#[C:33][Si:29]([CH3:32])([CH3:31])[CH3:30])=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(C#C[Si](C)(C)C)cc2)[nH]1)C(C)C
Temperature: 80 °C
Yield: 59.5 %

Procedure:
A solution of (1-{2-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (5.00 g, 11.1 mmol), TMS-acetylene (7.90 mL, 55.5 mmol) and triethylamine (4.64 mL, 33.3 mmol) in DMF (56 mL) was degassed with N2 gas for 20 minutes. To the degassed solution was added Pd(PPh3)4 (1.28 g, 1.11 mmol) and CuI (106 mg, 0.56 mmol). The pressure flask was sealed then heated at 80° C. overnight. After cooling to room temperature, the reaction was concentrated then diluted with EtOAc and washed with water. The aqueous phase was back-extracted two times then the organic phases were combined and dried over Na2SO4. After concentration, the crude material was purified by silica gel chromatography (10-80% EtOAc-hexanes gradient) to afford (2-methyl-1-{2-[5-(4-trimethylsilanylethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-propyl)-carbamic acid methyl ester (3.08 g, 6.60 mmol, 59% yield). LCMS-ESI+: calc'd for C25H35N4O3Si: 467.3 (M+H+). Found: 467.1 (M+H+).
Reaction SMILES: CN1C=C(CN(C)C(C2N(C3C=CC(F)=CC=3)C(S)=NC=2)=O)C(C)=N1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:37]([C:38]([O:40]CC)=[O:39])=[CH:36][N:35]=[C:34]2[S:43][CH2:44][C:45]2[C:50]([F:51])=[CH:49][CH:48]=[C:47]([F:52])[C:46]=2[F:53])=[CH:29][CH:28]=1.O.[OH-].[Li+].C1COCC1>O.CO>[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:37]([C:38]([OH:40])=[O:39])=[CH:36][N:35]=[C:34]2[S:43][CH2:44][C:45]2[C:50]([F:51])=[CH:49][CH:48]=[C:47]([F:52])[C:46]=2[F:53])=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1cnc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Agent: Cc1nn(C)cc1CN(C)C(=O)c1cnc(S)n1-c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1

Procedure:
1-(4-Fluorophenyl)-2-((2,3,6-trifluorobenzyl)thio)-1H-imidazole-5-carboxylic acid (11) was prepared in a similar manner as that described for the synthesis of compound 7 using ethyl 1-(4-fluorophenyl)-2-((2,3,6-trifluorobenzyl)thio)-1H-imidazole-5-carboxylate (10) (284 mg, 0.69 mmol), lithium hydroxide monohydrate (66 mg, 2.76 mmol), THF (0.2 mL), methanol (0.4 mL), and water (0.8 mL).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][O:13][C:14]2[C:19]([CH3:20])=[CH:18][C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:15]=2[CH3:24])(=O)=O)=CC=1.[CH:26]([NH2:29])([CH3:28])[CH3:27]>O1CCOCC1>[CH:26]([NH:29][CH2:11][CH2:12][O:13][C:14]1[C:15]([CH3:24])=[CH:16][C:17]([N+:21]([O-:23])=[O:22])=[CH:18][C:19]=1[CH3:20])([CH3:28])[CH3:27]
Reactant: Cc1ccc(S(=O)(=O)OCCOc2c(C)cc([N+](=O)[O-])cc2C)cc1
Reactant: CC(C)N
Solvent: C1COCCO1
Product: Cc1cc([N+](=O)[O-])cc(C)c1OCCNC(C)C
Temperature: 80 °C
Reaction time: 3 h

Procedure:
2-(2,6-Dimethyl-4-nitrophenoxy)ethyl p-toluenesulfonate (10.0 g) solution in dioxane (15 ml) was added with isopropylamine (10 ml) and the mixture was stirred for 3 hours in an autoclave at 80° C. After being concentrated , the reaction mixture was dissolved into ethyl acetate (50 ml) and extracted with 1N HCl (150 ml). Resultant aqueous layer was added with 1N sodium hydroxide (200 ml) and extracted with chloroform (200 ml). After being dehydrated with anhydrous magnesium sulfate (20 g), chloroform layer was concentrated under vacuum to dryness to obtain N-isopropyl-[2-(2,6-dimethyl-4-nitrophenoxy)]ethylamine (5.5 g) as yellowish solid.
Reaction SMILES: C[SiH](C)[C:3]1[CH:8]=[CH:7][CH:6]=CC=1.[SiH4].C(O[C:14]([CH3:17])([CH3:16])C)=C.[CH:18]([O:20]C=C)=C.C(OC(C)(C)C)(C)(C)C>O1CCOCC1>[CH2:18]([O:20][CH2:6][CH2:7][CH2:8][CH3:3])[CH2:17][CH2:14][CH3:16]
Reactant: C=COC(C)(C)C
Reactant: C=COC=C
Reactant: C[SiH](C)c1ccccc1
Agent: CC(C)(C)OC(C)(C)C
Agent: [SiH4]
Solvent: C1COCCO1
Product: CCCCOCCCC
Temperature: 25 °C

Procedure:
Into a 30 ml round-bottom flask with two necks equipped with a three-way cock, in which the air had been replaced with nitrogen gas, there were added 2.15 mg (3.3×10−3 mmol) of acenaphthylene heptacarbonyl ruthenium (the polynuclear ruthenium-carbonyl complex as expressed by the formula (V): hereinafter sometimes referred to simply as the “Ru complex”) as the catalyst, 0.05 ml of 1,4-dioxane as the solvent, and 0.050 ml (0.33 mmol) of dimethylphenylsilane (HSiMe2Ph) as the silane compound. After stirring at room temperature (25° C.) for thirty minutes, there was added 0.43 ml (3.3 mmol) of tert-butyl vinyl ether (tBuVE) as the vinyl ether compound. The resultant solution was stirred at room temperature for ten minutes, and then the 1,4-dioxane and the excess phenyldimethyl silane were distilled off. Into the residual viscous liquid was dissolved in 2 ml of hexane. Following the addition of methanol 6 ml, the resultant white deposit was subjected to drying in vacuo, to yield a white solid material, 277 mg (92%). The molecular weight of the white solid material was determined by GPC, and the material was also subjected to the measurement of IR, 1H and 13C NMR spectra. FIG. 2 shows the GPC chart. The assignment of the IR and NMR data are summarized below. From these results the white solid material was identified to be polyvinyl tert-butyl ether.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]=[C:10]2[CH2:14][CH2:13][O:12][C:11]2=[O:15])[CH:3]=1.C1(C)C(C)=CC=CC=1>C(O)(C(F)(F)F)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:11](=[O:15])[C:10]([CH2:14][CH2:13][OH:12])=[CH:9][N:8]=[C:4]2[CH:3]=1
Reactant: O=C1OCCC1=CNc1cc(Br)ccn1
Solvent: O
Solvent: Cc1ccccc1C
Solvent: O=C(O)C(F)(F)F
Product: O=c1c(CCO)cnc2cc(Br)ccn12
Temperature: 85 °C

Procedure:
In a small flask, 3-((4-bromopyridin-2-ylamino)methylene)dihydrofuran-2(3H)-one (250 mg, 0.93 mmol) and CF3COOH (8 drops) was added into a solution of xylene. The suspension was warmed to 85° C. and maintained at that temperature for 30 min. After the upper layer of suspension was poured out, the residue was diluted with water (30 mL) and adjusted to pH 8. Then the mixture was extracted with ethyl acetate (3×50 mL). The organic layer was dried over Na2SO4 and concentrated to give the crude product, which was purified by column chromatography. MS (ESI): 269, 271 (MH+).
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:17][CH2:18][CH2:19][CH3:20])=[C:6]([CH:14]=[CH:15][CH:16]=1)[CH2:7][N:8]([CH3:13])[C:9](=[O:12])[CH:10]=[CH2:11])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Br[C:31]1[CH:42]=[N:41][C:34]2[NH:35][C:36](=[O:40])[CH2:37][NH:38][CH2:39][C:33]=2[CH:32]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:1]([C:4]1[C:5]([O:17][CH2:18][CH2:19][CH3:20])=[C:6]([CH:14]=[CH:15][CH:16]=1)[CH2:7][N:8]([CH3:13])[C:9](=[O:12])/[CH:10]=[CH:11]/[C:31]1[CH:42]=[N:41][C:34]2[NH:35][C:36](=[O:40])[CH2:37][NH:38][CH2:39][C:33]=2[CH:32]=1)([CH3:3])[CH3:2]
Reactant: O=C1CNCc2cc(Br)cnc2N1
Reactant: C=CC(=O)N(C)Cc1cccc(C(C)C)c1OCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCOc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CNCC(=O)N3)cccc1C(C)C
Yield: 32.1 %

Procedure:
A solution of N-(3-isopropyl-2-propoxybenzyl)-N-methylacrylamide (0.385 g, 1.40 mmol) in propionitrile (5 mL) and DMF (1 mL) was deoxygenated with Ar for 20 min. The solution was treated with diisopropylethylamine (0.39 mL, 2.25 mmol) and 7-bromo-1,3,4,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-2-one (0.300 g, 1.07 mmol). The solution was deoxygenated with Ar for 20 min. Pd(OAc)2 (0.024 g, 0.10 mmol) and P(o-tol)3 (0.065 g, 0.21 mmol) were then added and the solution deoxygenated with Ar for 20 min. The solution was heated to reflux for 18 h, then allowed to cool. The solution was diluted with H2O (30 mL) and the mixture was washed with EtOAc (3×50 mL). The combined organics were washed with brine (2×100 mL), dried (Na2SO4) and concentrated. Purification by column chromatography (silica gel, CH2Cl2/MeOH, 100 to 95:5) gave the title compound (0.15 g, 33%) as an off-white solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.08-10.05 (m, 1H), 8.45-8.39 (m, 1H), 8.03-7.93 (m, 1H), 7.55-7.49 (m, 1H), 7.32-7.20 (m, 2H), 7.13-7.04 (m, 1H), 6.88-6.86 (m, 1H), 4.81-4.66 (m, 2H), 3.91-3.86 (m, 2H), 3.76-3.69 (m, 2H), 3.63-3.60 (m, 2H), 3.30-3.25 (m, 1H), 3.12-2.90 (m, 4H), 1.83-1.75 (m, 2H), 1.24-1.17 (m, 6H), 1.06-1.01 (m, 3H).
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH:16]2[CH:11]([CH2:12][CH2:13][NH:14][CH2:15]2)[CH2:10]1)=[O:8].Cl[C:24]1[N:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[N:25]=1.ClC1C=NC2C(=CC=CC=2)N=1>>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[C@@H:16]2[C@@H:11]([CH2:12][CH2:13][N:14]([C:24]3[N:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[N:25]=3)[CH2:15]2)[CH2:10]1)=[O:8]
Reactant: Cc1cc(C)nc(Cl)n1
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CCNCC21
Agent: Clc1cnc2ccccc2n1
Product: Cc1cc(C)nc(N2CC[C@H]3CN(C(=O)c4ccccc4-c4ccccc4)[C@H]3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S) biphenyl-2-yl-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)-methanone for biphenyl-2-yl-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)-methanone and 2-chloro-4,6-dimethyl-pyrimidine for 2-chloro quinoxaline. MS (ESI) mass calcd. for C25H26N4O, 398.50; m/z found 399.2 [M+H]+. 1H NMR (CDCl3): 7.54-7.31 (m, 7H), 7.25-7.11 (m, 2H), 6.33-6.23 (m 1H), 4.64-4.36 (0.5H), 4.00-3.39 (m, 5H), 3.25-2.85 (m, 1.25H), 2.60-2.37 (m, 1.25H), 2.33 (s, 3H), 2.25 (s, 3H), 2.00-1.37 (m, 2H).
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2([CH2:11][CH2:10]2)[CH2:8][N:7]([C@@H](C2C=CC=CC=2)C)[CH2:6]1)(=[O:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:4][CH:5]1[C:9]2([CH2:11][CH2:10]2)[CH2:8][NH:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)OC1CN([C@H](C)c2ccccc2)CC12CC2
Agent: [Pd]
Solvent: CCO
Product: CC(=O)OC1CNCC12CC2
Yield: 91.9 %

Procedure:
A suspension of 1.5 g of compound 12 and 500 mg of lithium aluminum hydride in 30 ml of tetrahydrofuran was refluxed for 16 hours. 0.5 ml of water, 0.5 ml of 15% aqueous sodium hydroxide and 1.5 ml of water were added to the mixture in the mentioned order, and the mixture was stirred at room temperature for 30 minutes. The insoluble material was removed by filtration and the filtrate was concentrated to dryness to yield 1.4 g of 7-hydroxy-5-[1-(R)-phenylethyl]-5-azaspiro[2,4]heptane as a pale yellow oil. 5 ml of acetic anhydride and 5 ml of pyridine were added to 1.4 g of 7-hydroxy-5-[1-(R)-phenylethyl]-5-azaspiro[2,4]heptane which was cooled on an ice-bath. The mixture was stirred at room temperature for 3 hours. Ethyl acetate was added thereto and the solution was washed with saturated aqueous sodium bicarbonate and water, then, dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to yield 1.6 g of 7-acetoxy-5-[1-(R)-phenylethyl]-5-azaspiro[2,4]heptane as a yellow oil. A mixture of 1.6 g of 7-acetoxy-5-[1-(R)-phenylethyl]-5-azaspiro[2,4]heptane and 1.2 g of palladium-on-carbon (50% water wet) in 20 ml of ethanol was shaken under 3.8 atm of pressured hydrogen atmosphere for 5 hours. During the reduction reaction, the reaction vessel was warmed by a tungsten lamp. The catalyst was removed by filtration and the solvent was removed under reduced pressure to give 880 mg of title compound 69 as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:7]([CH3:16])[C:6]=2[CH:17]=1.[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:16][C:7]1[C:6]2[CH:17]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[S:9][C:8]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(-c2ccccc2)sc2ccc(Cl)cc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc2sc(-c3ccccc3)c(CBr)c2c1

Procedure:
In a 100 ml round-bottomed flask, 1 eq. of the compound obtained in Step B is dissolved in 20 ml of CCl4. 1 eq. of N-bromosuccinimide and 0.04 eq. of benzoyl peroxide are then added, and the mixture is irradiated by means of a halogen lamp and maintained at reflux for 4 hours. At the end of the reaction, the insoluble material is filtered off, and the carbon tetrachloride is evaporated off. The residue obtained is purified by chromatography on a silica gel column.
Reaction SMILES: FC1C=CC(CNC)=CC=1.[F:11][CH:12]([F:23])[O:13][C:14]1[CH:22]=[CH:21][C:17]([CH2:18][NH:19][CH3:20])=[CH:16][CH:15]=1.[F:24][C:25]1[CH:47]=[CH:46][C:28]([CH2:29][NH:30][C:31]([C:33]2[S:37][C:36]([C:38]3[CH:43]=[N:42][CH:41]=[C:40](I)[N:39]=3)=[N:35][C:34]=2[CH3:45])=[O:32])=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:47]=[CH:46][C:28]([CH2:29][NH:30][C:31]([C:33]2[S:37][C:36]([C:38]3[CH:43]=[N:42][CH:41]=[C:40]([N:19]([CH2:18][C:17]4[CH:16]=[CH:15][C:14]([O:13][CH:12]([F:11])[F:23])=[CH:22][CH:21]=4)[CH3:20])[N:39]=3)=[N:35][C:34]=2[CH3:45])=[O:32])=[CH:27][CH:26]=1
Reactant: CNCc1ccc(OC(F)F)cc1
Reactant: Cc1nc(-c2cncc(I)n2)sc1C(=O)NCc1ccc(F)cc1
Agent: CNCc1ccc(F)cc1
Product: Cc1nc(-c2cncc(N(C)Cc3ccc(OC(F)F)cc3)n2)sc1C(=O)NCc1ccc(F)cc1
Yield: 80 %

Procedure:
Following the procedure described in Example 14, making variations as required to replace 4-fluoro-N-methyl-benzylamine with (4-difluoromethoxy-benzyl)-methyl-amine to react with 2-(6-iodo-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid 4-fluoro-benzylamide, the title compound was obtained in 80% yield. 1H NMR (400 MHz, CD2Cl2) δ 8.58 (s, 1H), 8.07 (s, 1H), 7.26-7.37 (m, 4H), 7.00-7.11 (m, 4H), 6.51 (bt, J=76, 64 Hz, 1H, CH—F signal), 6.16 (bs, 1H), 4.82 (s, 2H), 4.54 (d, J=8.0 Hz, 2H), 3.14 (s, 3H), 2.70 (s, 3H); MS (ES+) m/z 514.2 (M+1), Rt=1.63 min.
Reaction SMILES: ClC1C=C2[C:8](=[CH:9][CH:10]=1)[N:7](S(C1C=CC=CC=1)(=O)=O)C(C(OCC)=O)=C2S(Cl)(=O)=O.[I:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35](S(C1C=CC=CC=1)(=O)=O)[C:34]([C:48]([O:50]CC)=O)=[C:33]2[S:53](Cl)(=[O:55])=[O:54].Cl.CN.C1([NH2:63])CC1>>[I:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]([C:48]([NH2:63])=[O:50])=[C:33]2[S:53]([NH:7][CH:8]1[CH2:9][CH2:10]1)(=[O:54])=[O:55]
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(I)ccc2n1S(=O)(=O)c1ccccc1
Reactant: NC1CC1
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Agent: CN
Agent: Cl
Product: NC(=O)c1[nH]c2ccc(I)cc2c1S(=O)(=O)NC1CC1

Procedure:
Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-iodo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and methylamine hydrochloride with cyclopropylamine, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. ESI+ MS: 406.13 [M+H]+.