Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:12][NH:13][O:14][CH3:15].C(N(CC)CC)C.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>ClCCl.C1COCC1>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:13]([O:14][CH3:15])[CH3:12])=[O:5]
Reactant: O=C(O)c1cccnc1Cl
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
2-Chloro-nicotinic acid (10.0 g, 63.5 mmol, 1.0 equiv) is suspended in dichloromethane (400 mL) and THF (100 mL). N,O-Dimethyl-hydroxylamine hydrochloride (6.81 g, 69.8 mmol, 1.1 equiv) and triethylamine (9.70 mL, 69.8 mmol, 1.1 equiv) are added, resulting in a clear solution. The mixture is cooled in an ice bath and EDCI (13.4 g, 69.8 mmol, 1.1 equiv) and HOAt (0.86 g, 6.35 mmol, 0.1 equiv) are added. The resulting mixture is stirred overnight at room temperature and concentrated in vacuo. The residue is redissolved in ethyl acetate (200 mL) and washed with 1N NaOH solution, twice with sat. NaHCO3 solution and brine. The organic phase is dried over Na2SO4, filtered and concentrated in vacuo. This gives 7.53 g of the title compound as a white solid. Yield: 59%
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([NH2:11])[O:9][CH:10]=1)=[O:5])[CH3:2].[CH3:12][C:13]([CH3:15])=O.S(C)C.B>C1COCC1.CC(O)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][CH:13]([CH3:15])[CH3:12])[O:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CC(C)=O
Reactant: CCOC(=O)c1coc(N)n1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)c1coc(NC(C)C)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 63.1 %

Procedure:
A mixture of 2-aminooxazole-4-carboxylic acid ethyl ester (500 mg, 3.2 mmol) and acetone (2.4 mL, 32 mmol) in THF (6 mL) was stirred at rt. BH3.SMe2 (10M in THF, 0.64 mL, 6.4 mmol) was added slowly via syringe (exotherm and gas evolution were observed). AcOH (0.36 mL, 6.4 mmol) was subsequently added in the same manner. Two additional equivalents of borane and AcOH were added 18 h later. After 3 days at rt, the reaction mixture was concentrated in vacuo. The resulting residue was dissolved in EtOAc (100 mL), washed with saturated NH4Cl solution, 0.1 M NH4OH and brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel, eluting with EtOAc/hexane to give 2-isopropylamino-oxazole-4-carboxylic acid ethyl ester (0.40 g, 64% yield). LCMS found 199 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=1.CC(C)([O-])C.[K+]>C1COCC1>[CH:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[C:5]1[N:4]3[CH2:16][CH2:17][N:18]([C:19]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:25])[CH2:2][C:3]3=[N:15][C:6]=1[CH:7]=[N:8]2
Reactant: CC(C)(C)OC(=O)NCCn1c(CCl)nc2cnc3ccccc3c21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCn2c(nc3cnc4ccccc4c32)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 59.8 %

Procedure:
Under a nitrogen atmosphere, a solution of tert-butyl 2-[2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethylcarbamate (54.94 g, 152.3 mmol) in THF (400 mL) was cooled to 0° C.; a solution of potassium tert-butoxide (18.79 g of a 1 M solution in THF, 167.5 mmol) was added slowly. The reaction was stirred at 0° C. for three hours and then at ambient temperature overnight. The THF was removed under reduced pressure, and a 1:1 mixture of water and saturated aqueous sodium bicarbonate was added. The aqueous mixture was extracted with dichloromethane, and the combined extracts were washed sequentially with water and brine and concentrated under reduced pressure to provide 29.54 g of tert-butyl 10,11-dihydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinoline-9(8H)-carboxylate.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl.Cl[CH2:27][CH2:28][N:29]([CH3:31])[CH3:30]>CN(C=O)C>[CH3:30][N:29]([CH3:31])[CH2:28][CH2:27][O:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:5]2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3][B:2]([OH:1])[C:6]=2[CH:7]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(OCCN(C)C)cc(C)c21
Temperature: 90 °C

Procedure:
To the mixture of ethyl 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (200 mg, 0.8 mmol) in 15 ml DMF was added Cs2CO3 (782 mg, 2.4 mmol), followed by 2-chloro-N,N-dimethylethanamine hydrochloride (116 mg, 0.81 mmol). The mixture was heated to 90° C. for 6 h and quenched by ice water (20 mL). The resulting mixture was extracted with EtOAc (3×20 ml) and the combined organic layers were dried over anhydrous Na2SO4 and concentrated to dryness. The residue was used directly in next step reaction without further purification.
Reaction SMILES: Cl.[C:2]([NH:6][OH:7])(C)(C)[CH3:3].N1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:3]1([CH:2]=[NH+:6][O-:7])[C:12]2[C:11]([CH:12]=[CH:13][CH:9]=[CH:10][CH:11]=2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)NO
Reactant: c1ccncc1
Agent: Cl
Product: [O-][NH+]=Cc1ccc2cccccc1-2
Temperature: 95 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A carboxaldehdye group is converted readily to, for example, a N-tert-butyl nitrone group, by the following method: To a 0.2M solution of the aldehyde obtained by Procedure B in dry pyridine under argon at rt is added solid N-tert-butylhydroxylamine hydrochloride (1.5-2.0 eq). The mixture is heated with stirring to 95° C. for one hour and then allowed to cool to rt. The pyridine is removed on the rotary evaporator, and the residue is dissolved in CHCl3. The CHCl3 layer is washed with water and dried over MgSO4. Evaporation of the CHCl3 followed by silica gel chromatography of the residue (CHCl3 :MeOH) provides the solid green azulenyl nitrone in 96% yield.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2]>O1CCCC1.[C].[Pd]>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)/C=C/c1ccc(C#N)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(C#N)cc1
Yield: 97.6 %

Procedure:
(E)-Ethyl 3-(4-cyanophenyl)acrylate (13.9 g, 69.1 mmol) in tetrahydrofuran (100 ml) was hydrogenated over 10% Palladium-Carbon (4.00 g) at atmospheric pressure. After removal of the catalyst, the filtrate was concentrated in vacuo to give ethyl 3-(4-cyanophenyl)propionate as a yellow oil (13.7 g, 98%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[C:14]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=2)[C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH3:28][O:29][C:30]1[N:35]=[C:34]([O:36][CH3:37])[CH:33]=[C:32]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[N:31]=1>N1C=CC=CC=1>[CH3:28][O:29][C:30]1[N:31]=[C:32]([N:38]2[CH2:43][CH2:42][N:41]([C:2]3[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]4[CH:13]=[C:14]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=4)[C:3]=3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:40][CH2:39]2)[CH:33]=[C:34]([O:36][CH3:37])[N:35]=1
Reactant: NS(=O)(=O)c1cccc(-c2nc(C(F)(F)F)nc(Cl)c2-c2ccccc2)c1
Reactant: COc1cc(N2CCNCC2)nc(OC)n1
Solvent: c1ccncc1
Product: COc1cc(N2CCN(c3nc(C(F)(F)F)nc(-c4cccc(S(N)(=O)=O)c4)c3-c3ccccc3)CC2)nc(OC)n1
Reaction time: 8 h

Procedure:
A solution of 3-[6-chloro-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl]benzenesulfonamide (0.1 g, 0.24 mmol) in pyridine (1.5 ml) was treated with 2,4-dimethoxy-6-piperazin-1-ylpyrimidine (0.081 g, 0.363 mmol) and the reaction mixture was stirred for 8 hours. Subsequently the reaction mixture was poured onto ice-cold water and extracted with ethyl acetate (25 ml). The organic layer was washed with brine and evaporated to furnish the title compound. 1H-NMR (CDCl3) δ: 3.39-3.41 (m, 4H), 3.51-3.52 (m, 4H), 3.87-3.88 (s, 6H), 7.07-7.09 (d, 2H), 7.20-7.26 (m, 3H), 7.30-7.32 (m, 1H), 7.47-7.61 (t, 1H), 7.64 (s, 1H), 7.82-7.87 (m, 2H); MS m/z: 601.8 (M+).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH:16]=[CH:17][CH2:18]O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:20][C:21]1[CH:33]=[C:32]([C:34]#[N:35])[CH:31]=[CH:30][C:22]=1[NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH:16]=[CH:17][CH2:18][N:23]([C:22]1[CH:30]=[CH:31][C:32]([C:34]#[N:35])=[CH:33][C:21]=1[Br:20])[C:24](=[O:29])[C:25]([F:26])([F:27])[F:28])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1C=CCO
Reactant: N#Cc1ccc(NC(=O)C(F)(F)F)c(Br)c1
Product: N#Cc1ccc(N(CC=C[C@H]2CCCN2C(=O)OCc2ccccc2)C(=O)C(F)(F)F)c(Br)c1

Procedure:
(R)-1-(N-Benzyloxycarbonylpyrrolidin-2-yl)-3-hydroxypropene and 2-bromo-4-cyano-N-trifluoroacetylaniline were used. Column chromatography using elution with a gradient of diethyl ether (5%-100%) in methylene chloride afforded the title compound as a clear, colorless oil: IR (CHCl3) 2231, 1702, 1157 cm-1 ; LRMS (m/z, relative intensity) 537 ([MH+ with 81Br], 13), 535 ([MH+ with 79Br], 13), 402 (29), 400 (30), 294 (55), 292 (57), 244 (80), 213 (89), 91 (100); Anal. calcd for C24BrF3H21N3O3 ·0.2 H2O: C, 53.39; H, 3.99; N, 7.78. Found: C, 53.25; H, 3.95; N, 7.98.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][CH2:7][N:8]1[C:13]([CH3:14])=[CH:12][N:11]=[C:10](O)[C:9]1=[O:16])=[O:5].P(Br)(Br)([Br:19])=O.N#N.[OH-].[NH4+]>ClCCl.C(Cl)(Cl)Cl.O>[CH3:1][CH2:2][O:3][C:4]([CH2:6][CH2:7][N:8]1[C:13]([CH3:14])=[CH:12][N:11]=[C:10]([Br:19])[C:9]1=[O:16])=[O:5]
Reactant: CCOC(=O)CCn1c(C)cnc(O)c1=O
Reactant: O=P(Br)(Br)Br
Agent: N#N
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)CCn1c(C)cnc(Br)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
To a stirred slurry of 1-[(2-ethoxycarbonyl)ethyl]-3-hydroxy-6-methylpyrazinone (2-6) (3.8 g, 16.8 mmol) in 20 mL of dichloromethane, phosphorous oxybromide (5.8 g, 20.2 mmol) was added at 50° C. under a steady stream of N2. The resulting mixture was stirred for 2 hours. The reaction mixture was allowed to cool to room temperature and stirring was continued overnight. The mixture was diluted with 30 mL of chloroform and 30 mL of cold water, basified with ammonium hydroxide, and extracted with 30 mL of chloroform (3×). The combined organic layers were dried over anhydrous sodium sulfate, and concentrated in vacuo to yield the title compound (3.8 g, 80%) as an orange solid; the product was verified by NMR. 1H NMR (CDCl3): δ 7.01 (s, 1H), 4.26 (q, 2H), 4.16 (q, 2H), 2.83 (t, 2H), 2.38 (s, 3H), 1.25 (t, 3H).
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]([CH:7]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:8]1)=[O:6])[CH3:3].[C:16]1([CH3:23])[C:21]([OH:22])=[CH:20][CH:19]=[CH:18][CH:17]=1.[H-].[Na+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[OH:8][CH:7]([CH:9]([O:22][C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:23])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:5]([NH:4][CH:2]([CH3:1])[CH3:3])=[O:6]
Reactant: Cc1ccccc1O
Reactant: CC(C)NC(=O)C1OC1c1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccccc1OC(c1ccccc1)C(O)C(=O)NC(C)C

Procedure:
This compound was prepared from N-(1-methylethyl)-3-phenyl-2-oxiranecarboxamide (8.2 g.) o-cresol (4.3 g.), sodium hydride (50% oil dispersion, 1.9 g.), 18-crown-6 (1.0 g.), and acetonitrile (250 ml.) as described in Example 12. The compound after recrystallization from ether melted at 123°-124°, and weighed 1.25 g.
Reaction SMILES: [C:1]([N:5]([N:9]1[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][CH:11]([NH2:28])[C:10]1=[O:29])[C:6](=[O:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].[C:30]1([CH3:39])[CH:35]=[CH:34][CH:33]=[C:32]([N:36]=[C:37]=[O:38])[CH:31]=1>C(OCC)(=O)C>[C:1]([N:5]([N:9]1[CH:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:14][CH:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][CH:11]([NH:28][C:37]([NH:36][C:32]2[CH:31]=[C:30]([CH3:39])[CH:35]=[CH:34][CH:33]=2)=[O:38])[C:10]1=[O:29])[C:6](=[O:8])[CH3:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cccc(N=C=O)c1
Reactant: CC(=O)N(N1C(=O)C(N)CC(c2ccccc2)CC1c1ccccc1)C(C)(C)C
Solvent: CCOC(C)=O
Product: CC(=O)N(N1C(=O)C(NC(=O)Nc2cccc(C)c2)CC(c2ccccc2)CC1c1ccccc1)C(C)(C)C

Procedure:
To a 35 mL round-bottomed flask equipped with N2 inlet and condenser were added 293 mg (0.745 mmol) (-)-1-(N-t-butylacetamido)-3-amino-5,7-diphenylhexahydroazepin-2-one, 10 mL ethyl acetate, and 0.096 mL (0.745 mmol) m-tolylisocyanate. The reaction was refluxed for 2.5 hr, cooled, and evaporated. The residue was chromatographed on silica gel using hexane/ethyl acetate as eluant to afford an oil which was crystallized from methylene chloride/isopropyl ether to a give mp 140°-150° C., 71 mg (18%), αD =-18.6° (c=1, CH2Cl2). The Rf value on TLC and 1H-NMR spectrum match those of the racemate.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[F:15][C:16]([F:29])([F:28])[C:17]1[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=1)[CH:20]=[CH:21][C:22](O)=O>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:22](/[CH:21]=[CH:20]/[C:19]3[CH:25]=[CH:26][CH:27]=[C:17]([C:16]([F:15])([F:28])[F:29])[CH:18]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: O=C(O)C=Cc1cccc(C(F)(F)F)c1
Product: CCn1c(=O)c2[nH]c(/C=C/c3cccc(C(F)(F)F)c3)nc2n(CC)c1=O
Yield: 43.4 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.50 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 3.0 g (13.9 mmol) of 3-trifluoromethylcinnamic acid. Then, the resultant crude crystals were recrystallized from acetonitrile/water to give 2.07 g (yield 44%) of Compound 156 as white needles.
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[C:10](=[O:23])[C:9](=O)[CH2:8]2)[CH:2]=1.[CH3:26][C:27]([NH2:39])([C:29]1[CH:30]=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=1)[CH3:28].N#N>C1(C)C=CC=CC=1>[CH3:28][C:27]([NH:39][C:9]1[C:10](=[O:23])[N:11]([C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19]([F:21])([F:20])[F:22])=[CH:16][CH:17]=2)[CH:7]([C:3]2[CH:2]=[C:1]([CH3:25])[CH:6]=[CH:5][CH:4]=2)[CH:8]=1)([C:29]1[CH:30]=[N:31][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:33][CH:34]=1)[CH3:26]
Reactant: Cc1cccc(C2CC(=O)C(=O)N2c2ccc(OC(F)(F)F)cc2)c1
Reactant: CC(C)(N)c1ccc(C(F)(F)F)nc1
Agent: N#N
Solvent: Cc1ccccc1
Product: Cc1cccc(C2C=C(NC(C)(C)c3ccc(C(F)(F)F)nc3)C(=O)N2c2ccc(OC(F)(F)F)cc2)c1
Temperature: 80 °C
Yield: 40.1 %

Procedure:
Charge toluene (20 mL) to a flask containing (±)-5-m-tolyl-1-(4-trifluoromethoxy-phenyl)-pyrrolidine-2,3-dione (4.13 g; 11.82 mmol). Add 1-methyl-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamine (4.83 g, 23.65 mmol) to the above solution in an atmosphere of N2. Heat the reaction mixture to 80° C. for 24 hours. Cool to ambient temperature and evaporate in vacuo. Dissolve in MeOH (90 mL) and pass through an SCX-2 ion exchange resin cartridge. Evaporate the MeOH wash to give the crude product. Purify on an SCX-2 ion exchange resin cartridge (eluent with methanol) and then by chromatography on a silica gel column eluting with iso-hexane/ethyl acetate (80:20) to afford the titled compound (2.54 g, 58%). MS (m/z): 536.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:14]([O:16][CH3:17])=[O:15])([CH3:13])[CH2:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>CCOCC>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([N:10]2[CH2:11][C:12]([C:14]([O:16][CH3:17])=[O:15])([CH3:13])[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:9]2)=[O:27])=[CH:21][CH:20]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COC(=O)C1(C)CNN=C1c1ccc(Cl)cc1
Solvent: CCOCC
Product: COC(=O)C1(C)CN(C(=O)Nc2ccc(Cl)cc2)N=C1c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 96 %

Procedure:
An ether solution of 3-(4-chlorophenyl)-4-carbomethoxy-4-methyl-4,5-dihydro-1H-pyrazole (Example O) (approximately 1.8 mole) is treated with 286 g (1.86 mole) of 4-chlorophenyl isocyanate at a rate sufficient to maintain a mild reflux. After stirring for 30 minutes solvent is removed to 2/3 of the volume to afford a semisolid. After cooling in an ice bath solid product is filtered and washed with cold hexane and dried yielding 702 g (95%) of N,3-bis-(4-chlorophenyl)-4-carbomethoxy-4-methyl-4,5-dihydro-1H-pyrazole-1-carboxamide. NMR data was consistent with the structure.
Reaction SMILES: O=[C:2]1[CH:10]([C:11]#[N:12])[CH2:9][CH2:8][C:3]21[S:7][CH2:6][CH2:5][S:4]2.[C:13]1([C:19]2[N:24]=[CH:23][C:22]([C:25]3[CH:26]=[N:27][NH:28][C:29]=3[NH2:30])=[CH:21][CH:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[C:13]1([C:19]2[N:24]=[CH:23][C:22]([C:25]3[CH:26]=[N:27][N:28]4[C:11]([NH2:12])=[C:10]5[CH2:9][CH2:8][C:3]6([S:7][CH2:6][CH2:5][S:4]6)[C:2]5=[N:30][C:29]=34)=[CH:21][CH:20]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N#CC1CCC2(SCCS2)C1=O
Reactant: Nc1[nH]ncc1-c1ccc(-c2ccccc2)nc1
Solvent: Cc1ccccc1
Product: Nc1c2c(nc3c(-c4ccc(-c5ccccc5)nc4)cnn13)C1(CC2)SCCS1
Temperature: 115 °C

Procedure:
A mixture of 6-oxo-1,4-dithiaspiro[4.4]nonane-7-carbonitrile (485 mg, 2.27 mmol) and 4-(6-phenylpyridin-3-yl)-1H-pyrazol-5-amine (537 mg, 2.27 mmol) in toluene (10 mL) was heated at 115° C. overnight. Concentration afforded crude 3-(6-phenylpyridin-3-yl)-6,7-dihydrospiro[cyclopenta[d]pyrazolo[1,5-a]pyrimidine-5,2′-[1,3]dithiolan]-8-amine, which was converted to 8-amino-3-(6-phenylpyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrazolo[1,5-a]pyrimidin-5-one applying Stork's procedure (G. Stork, K. Zhao, Tetrahedron Letter, 1989, 30, 287) by treating with PhI(OCF3)2. LCMS tR=1.07 Min (5 min run, UV254nm), Mass calculated for, M+341.1, observed LC/MS m/z 342.1 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([CH3:17])[CH2:14][C@@H:13]([NH:18]C(OC(C)(C)C)=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:26].O1CCOCC1>C(Cl)Cl>[ClH:26].[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([CH3:17])[CH2:14][C@@H:13]([NH2:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1C[C@@H](NC(=O)OC(C)(C)C)CN(C(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H]1C[C@@H](N)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
(3R,5R)-3-tert-Butoxycarbonylamino-5-methyl-piperidine-1-carboxylic acid benzyl ester (3.25 g, 9.327 mmol) was dissolved in DCM (50 mL) and HCl 4M in dioxane (20 mL, 80 mmol) was added. The resulting colorless solution stirred at RT for 4 hours before being evaporated. The residue was dried under high vacuum overnight to give 2.89 g of (3R,5R)-3-amino-5-methyl-piperidine-1-carboxylic acid benzyl ester hydrochloride as a white foam (>95% yield).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:28]=[C:27]([CH2:29][N:30]4[CH2:35][CH2:34][CH:33]([C:36]([OH:39])([CH3:38])[CH3:37])[CH2:32][CH2:31]4)[S:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:3][CH2:2]1.I[C:41]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[NH:43][N:42]=1>O1CCOCC1.S1C=CC=C1C([O-])=O.[Cu+].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>[NH:43]1[C:44]2[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:41]([C:11]2[N:12]=[C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[C:8]3[N:28]=[C:27]([CH2:29][N:30]4[CH2:35][CH2:34][CH:33]([C:36]([OH:39])([CH3:38])[CH3:37])[CH2:32][CH2:31]4)[S:26][C:9]=3[N:10]=2)=[N:42]1
Reactant: Ic1n[nH]c2ccccc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)sc2n1
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: CC(C)(O)C1CCN(Cc2nc3c(N4CCOCC4)nc(-c4n[nH]c5ccccc45)nc3s2)CC1
Yield: 27.2 %

Procedure:
A mixture of 2-(1-((7-morpholino-5-(tributylstannyl)thiazolo[5,4-d]pyrimidin-2-yl)methyl)piperidin-4-yl)propan-2-ol (0.211 g, 0.32 mmol), 3-iodo-1H-indazole (0.116 g, 0.48 mmol), copper(I) 2-thiophene carboxylate (0.012 g, 0.064 mmol) and Pd(PPh3)4 (0.037 g, 0.032 mmol) in dioxane (3 mL)was subjected to microwave irradiation at 150° C. for 90 min. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH. The eluent was concentrated in vacuo and the resultant residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 10:90) to give 209 as a yellow solid (0.043 g, 28%). LCMS (Method G): RT=7.71 min, [M+H]+ 494.3. 1H NMR (400 MHz, DMSO-d6): δ 13.45 (s, 1 H); 8.48 (d, J=8.3 Hz, 1 H); 7.61 (d, J=8.3 Hz, 1 H); 7.41 (t, J=7.6 Hz, 1 H); 7.26 (t, J=7.6 Hz, 1 H); 4.37 (m, 4 H); 3.88 (s, 2 H); 3.82 (t, J=4.6 Hz, 4 H); 3.02 (d, J=11.0 Hz, 2 H); 2.12 (t, J=11.0 Hz, 2 H); 1.74-1.69 (m, 2 H); 1.36-1.28 (m, 2 H); 1.26-1.23 (m, 2 H); 1.06 (s, 6 H)
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:24])[C@H:10]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH:11][C:12](=[O:16])[C:13](=O)[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:13](=[CH2:14])[C:12](=[O:16])[NH:11][C@@H:10]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)NCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C=C1C(=O)N[C@@H](Cc2ccccc2)C(=O)N1Cc1ccccc1
Yield: 52.6 %

Procedure:
Using a Dean-Stark trap whose trap part was filled with molecular sieves 3A, a solution of N-2-oxo-propanoyl-L-phenylalanine benzylamide from Example 3a (100 mg, 0.31 mmol) in toluene (20 mL) was refluxed in the presence of p-TsOH.H2O (1.8 mg, 0.0093 mmol, 0.03 eq) for 24 h. After removal of the solvent, the residue was purified by a silica gel chromatography to yield 50 mg (53%) of title compound as a white solid: mp 124-127° C., 1H NMR (300 MHz, CDCl3) δ 7.01-7.35 (m, 10H), 6.84 (br s, 1H), 5.60 (s, 1H), 5.01 (d, J=15.7 Hz, 1H), 4.85 (d, J=15.7 Hz, 1H), 4.76 (s, 1H), 4.49-4.52 (m, 1H), 3.36 (dd, J=3.7, 13.6 Hz, 1H), 3.12 (dd, J=7.7, 13.6 Hz, 1H); HRMS (EI): m/z 306.1369 (M+) (calcd for C19H18N2O2: 306.1368). Enantiomeric excess was determined to be >99% using chiral HPLC with a CHIRALCEL OD column.